# NM_207361.6(FREM2):c.6036C>T (p.Phe2012=)

https://sugi.bio/variant/frem2-p-phe2012

## Summary

**FREM2 p.Phe2012= (c.6036C>T)** is classified **Benign/Likely benign** in FREM2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Low-frequency (popmax 2.69%, afr); Associated with Fraser syndrome 2.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs115455037 · 6 submitters · 2 linked conditions · low-frequency (popmax 2.69%, afr)

## For patients & families {#patients}

This is a change in the FREM2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 6 submitters, and is linked to Fraser syndrome 2.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025963/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FREM2](https://sugi.bio/atlas/gene/FREM2/) |
| Protein change (HGVS p.) | p.Phe2012= |
| Coding change (HGVS c.) | c.6036C>T |
| MANE Select transcript | [NM_207361](https://www.ncbi.nlm.nih.gov/nuccore/NM_207361) |
| dbSNP | [rs115455037](https://www.ncbi.nlm.nih.gov/snp/rs115455037/) |
| Variant type | single nucleotide variant |
| Location | chr13:38846589-38846589 (GRCh38) |
| ClinVar | [VCV312001](https://www.ncbi.nlm.nih.gov/clinvar/variation/312001/) |

**All HGVS expressions:** `NC_000013.10:g.39420726C>T`, `NC_000013.11:g.38846589C>T`, `NG_008125.2:g.164554C>T`, `NM_207361.6:c.6036C>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 (below), not from a missing predictor score.
- Conservation: phyloP -5.716, GERP -5.44 — fast-evolving / accelerated position
- CADD: **PHRED 0.423**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.96 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **2.69%** (afr) · FAF95 2.6% · FAF99 2.56% · 2,021/74,996 in the highest group · 2,395/1,613,550 alleles overall — low-frequency (popmax 2.69%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 2.69% | 37 |
| Admixed American | 0.262% | 382 |
| Remaining individuals (not grpmax-eligible) | 0.168% | 595 |
| Middle Eastern | 0.0502% | 1,994 |
| South Asian | 0.0132% | 7,589 |
| Finnish (not grpmax-eligible) | 0.0109% | 9,139 |
| European (non-Finnish) | 0.00754% | 13,255 |
| East Asian | 0.00223% | 44,840 |

*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}

**FREM2** population constraint: LOEUF 0.588, pLI 2.3417e-11, missense-Z 0.88478. *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 **2012** lies in the calx-beta 3 domain; a UniProt-annotated variant site (in cryptop).

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (4 Benign, 2 Likely benign).

**Submission history:** 6 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-07-21 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2020-01-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-27 |

## Associated conditions {#conditions}

[Fraser syndrome 2](https://sugi.bio/atlas/disease/fraser-syndrome-2/), [isolated cryptophthalmia](https://sugi.bio/atlas/disease/isolated-cryptophthalmia/).

**Reported phenotype names (ClinVar):** Fraser syndrome 2, not provided, Isolated cryptophthalmia, FREM2-related disorder, FREM2-related condition, Cryptophthalmos, unilateral or bilateral, isolated, ANKYLOBLEPHARON, SIMPLE, none provided.

## Similar variants {#similar}

Related FREM2 variant pages (same residue, condition, or type): [FREM2 p.Arg1355Ter](/variant/frem2-p-arg1355ter), [FREM2 p.Arg638Ter](/variant/frem2-p-arg638ter), [FREM2 p.Arg736Ter](/variant/frem2-p-arg736ter), [FREM2 p.Arg809Ter](/variant/frem2-p-arg809ter), [FREM2 p.Gln1051Ter](/variant/frem2-p-gln1051ter), [FREM2 p.Gln717Ter](/variant/frem2-p-gln717ter), [FREM2 p.Ala1659Thr](/variant/frem2-p-ala1659thr), [FREM2 p.Ala1664Val](/variant/frem2-p-ala1664val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 312001). 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.*