# NM_024329.6(EFHD2):c.452G>A (p.Arg151Gln)

https://sugi.bio/variant/efhd2-p-arg151gln

## Summary

**EFHD2 p.Arg151Gln (c.452G>A)** is classified **Uncertain significance** in EFHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-14). AlphaMissense: ambiguous (0.5579); Ultra-rare (popmax 0.0137%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · ultra-rare (popmax 0.0137%, afr)

## For patients & families {#patients}

This is a change in the EFHD2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [EFHD2](https://sugi.bio/atlas/gene/EFHD2/) |
| Protein change (HGVS p.) | p.Arg151Gln |
| Coding change (HGVS c.) | c.452G>A |
| MANE Select transcript | [NM_024329](https://www.ncbi.nlm.nih.gov/nuccore/NM_024329) |
| Variant type | single nucleotide variant |
| Location | chr1:15426014-15426014 (GRCh38) |
| ClinVar | [VCV3507024](https://www.ncbi.nlm.nih.gov/clinvar/variation/3507024/) |

**All HGVS expressions:** `NC_000001.10:g.15752510G>A`, `NC_000001.11:g.15426014G>A`, `NG_089475.1:g.55G>A`, `NM_024329.6:c.452G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.5579) — no call either way
- REVEL 0.514 (indeterminate)
- SaProt LLR -8.913 (tolerated)
- Conservation: phyloP 11.79, GERP 2.37, phastCons 1 — highly conserved
- CADD: **PHRED 33.0**. 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.*
- Regional missense constraint: **o/e 0.25** across the covering region of the MANE Select transcript (15,425,957–15,427,156), spanning 1,199 bp — the region is depleted of missense variation. Chi-square p 9.1e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0137%** (afr) · FAF95 0.00742% · FAF99 0.00564% · 10/72,810 in the highest group · 14/1,581,076 alleles overall — ultra-rare (popmax 0.0137%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0137% | 7,281 |
| Remaining individuals (not grpmax-eligible) | 0.00328% | 30,528 |
| European (non-Finnish) | 0.000172% | 582,798 |

*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}

**EFHD2** population constraint: LOEUF 1.182, pLI 0.00065333, missense-Z 0.95416. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **151** lies in an α-helix; the ef-hand 2 domain.

AlphaFold model confidence (whole protein): pLDDT 75.28, 26% of residues very-high.

**5 experimental structure(s)** (PDB): [5H0P](https://www.rcsb.org/structure/5H0P), [5I2L](https://www.rcsb.org/structure/5I2L), [5I2O](https://www.rcsb.org/structure/5I2O), [5I2Q](https://www.rcsb.org/structure/5I2Q), [7YGY](https://www.rcsb.org/structure/7YGY) — incl. mutant structure 5H0P.

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

*Describes the biological roles of EFHD2 (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:** EFHD2's established molecular role includes cadherin binding. p.Arg151Gln falls in the ef-hand 2 domain.


### Pathways affected {#pathways}

EFHD2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RHOD GTPase cycle](https://reactome.org/content/detail/R-HSA-9013405) | curated |

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

**Molecular function:** cadherin binding, actin filament binding, calcium ion sensor activity.

**Biological process:** actin crosslink formation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-14.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-14 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related EFHD2 variant pages (same residue, condition, or type): [EFHD2 p.Ala160Val](/variant/efhd2-p-ala160val), [EFHD2 p.Ala161Val](/variant/efhd2-p-ala161val), [EFHD2 p.Ala200Thr](/variant/efhd2-p-ala200thr), [EFHD2 p.Ala37Val](/variant/efhd2-p-ala37val), [EFHD2 p.Ala44Val](/variant/efhd2-p-ala44val), [EFHD2 p.Ala45Thr](/variant/efhd2-p-ala45thr), [EFHD2 p.Ala51Val](/variant/efhd2-p-ala51val), [EFHD2 p.Arg176Cys](/variant/efhd2-p-arg176cys).

### 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 3507024). 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.*