# NM_001039348.3(EFEMP1):c.159C>T (p.Asp53=)

https://sugi.bio/variant/efemp1-p-asp53

## Summary

**EFEMP1 p.Asp53= (c.159C>T)** is classified **Benign/Likely benign** in EFEMP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-29). Ultra-rare (popmax 0.0401%, eas).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs17047322 · 2 submitters · ultra-rare (popmax 0.0401%, eas)

## For patients & families {#patients}

This is a change in the EFEMP1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 2 submitters.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EFEMP1](https://sugi.bio/atlas/gene/EFEMP1/) |
| Protein change (HGVS p.) | p.Asp53= |
| Coding change (HGVS c.) | c.159C>T |
| MANE Select transcript | [NM_001039348](https://www.ncbi.nlm.nih.gov/nuccore/NM_001039348) |
| dbSNP | [rs17047322](https://www.ncbi.nlm.nih.gov/snp/rs17047322/) |
| Variant type | single nucleotide variant |
| Location | chr2:55918023-55918023 (GRCh38) |
| ClinVar | [VCV1166128](https://www.ncbi.nlm.nih.gov/clinvar/variation/1166128/) |

**All HGVS expressions:** `NC_000002.11:g.56145158G>A`, `NC_000002.12:g.55918023G>A`, `NG_009098.1:g.10775C>T`, `NM_001039348.3:c.159C>T`, `NM_001039349.3:c.159C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.22) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -8.646, GERP -5.15 — fast-evolving / accelerated position
- CADD: **PHRED 7.491**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0401%** (eas) · FAF95 0.0259% · FAF99 0.0214% · 18/44,884 in the highest group · 50/1,614,162 alleles overall — ultra-rare (popmax 0.0401%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0401% | 2,494 |
| Middle Eastern | 0.0165% | 6,062 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,254 |
| African / African-American | 0.00267% | 37,511 |
| European (non-Finnish) | 0.00212% | 47,201 |
| Admixed American | 0.00167% | 60,024 |
| South Asian | 0.0011% | 91,080 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**EFEMP1** population constraint: LOEUF 0.373, pLI 1, missense-Z 2.7165. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **open-angle glaucoma** — Moderate (AD)
- **Doyne honeycomb retinal dystrophy** — Definitive (AD)

## Protein context {#protein}

Residue **53** lies in the egf-like 1; atypical domain.

AlphaFold model confidence (whole protein): pLDDT 77.67, 47% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of EFEMP1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** EFEMP1's established molecular role includes epidermal growth factor receptor activity. p.Asp53= falls in the egf-like 1; atypical domain.


### Pathways affected {#pathways}

EFEMP1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Molecules associated with elastic fibres](https://reactome.org/content/detail/R-HSA-2129379) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** epidermal growth factor receptor activity, epidermal growth factor receptor binding.

**Biological process:** regulation of DNA-templated transcription, epidermal growth factor receptor signaling pathway, peptidyl-tyrosine phosphorylation, negative regulation of chondrocyte differentiation, camera-type eye development, embryonic eye morphogenesis.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-29.

**Submitter consensus:** conflicting (1 Benign, 1 Likely benign).

**Submission history:** 2 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-09-29 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-20 |

**Reported phenotype names (ClinVar):** not provided, not specified, AllHighlyPenetrant, none provided.

## Same-residue context {#hotspot}

Residue **53** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [EFEMP1 p.Asp53fs](/variant/efemp1-p-asp53fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related EFEMP1 variant pages (same residue, condition, or type): [EFEMP1 p.Asp53fs](/variant/efemp1-p-asp53fs), [EFEMP1 p.Arg345Trp](/variant/efemp1-p-arg345trp), [EFEMP1 p.Ala104Thr](/variant/efemp1-p-ala104thr), [EFEMP1 p.Ala126Pro](/variant/efemp1-p-ala126pro), [EFEMP1 p.Ala126Thr](/variant/efemp1-p-ala126thr), [EFEMP1 p.Ala447Ser](/variant/efemp1-p-ala447ser), [EFEMP1 p.Ala447Thr](/variant/efemp1-p-ala447thr), [EFEMP1 p.Arg148His](/variant/efemp1-p-arg148his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1166128). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*