Is FREM2 p.Arg1344Ser (c.4030C>A) pathogenic?

FREM2 p.Arg1344Ser (c.4030C>A) is classified Uncertain significance in FREM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-09). AlphaMissense: likely pathogenic (0.8115); Ultra-rare (popmax 0.0703%, sas); Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Arg1344Ser (c.4030C>A)?

FREM2 p.Arg1344Ser (c.4030C>A) is associated with Fraser syndrome 2, isolated cryptophthalmia (ClinVar).

How common is FREM2 p.Arg1344Ser (c.4030C>A) in the general population?

FREM2 p.Arg1344Ser (c.4030C>A) is ultra-rare (popmax 0.0703%, sas) (gnomAD).

What do computational predictors say about FREM2 p.Arg1344Ser (c.4030C>A)?

AlphaMissense predicts likely pathogenic (score 0.8115) — an in-silico prediction, not a clinical call.

FREM2 p.Arg1344Ser

c.4030C>A · VCV3576077

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8115 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0703%, sas)

Conditions

Fraser syndrome 2

Computational evidence

Protein change
AlphaMissense	0.8115	likely pathogenic
REVEL	0.317	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0703% South Asian · 64/91,046 alleles

Filtering AF 0.0565% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0515%

Overall 0.00428% 69/1,613,772 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0703%	1,423
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0032%	31,248
European (non-Finnish)	0.00017%	589,877

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FREM2
Protein: p.Arg1344Ser
Coding: c.4030C>A
MANE Select: NM_207361
Type: single nucleotide variant
Location: chr13:38691374 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 1344: a UniProt-annotated variant site (in cryptop)

Full FREM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Fraser syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: isolated cryptophthalmia

Similar variants

FREM2 p.Arg1344His Benign/Likely benign ★★ same residue
FREM2 p.Arg1344Cys Uncertain significance ★ same residue
FREM2 p.Arg1344= Likely benign ★ same residue
FREM2 p.Arg1355Ter Pathogenic/Likely pathogenic ★★ same condition
FREM2 p.Arg638Ter Likely pathogenic ★★ same condition
FREM2 p.Arg736Ter Pathogenic ★★ same condition
FREM2 p.Arg809Ter Pathogenic ★★ same condition
FREM2 p.Gln1051Ter Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/frem2-p-arg1344ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown