Is FREM2 p.Arg2273Ser (c.6819A>C) pathogenic?

FREM2 p.Arg2273Ser (c.6819A>C) is classified Uncertain significance in FREM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-24). AlphaMissense: likely benign (0.1479); Very rare (popmax 0.00695%, nfe); Associated with isolated cryptophthalmia.

What condition is associated with FREM2 p.Arg2273Ser (c.6819A>C)?

FREM2 p.Arg2273Ser (c.6819A>C) is associated with isolated cryptophthalmia, Fraser syndrome 2 (ClinVar).

How common is FREM2 p.Arg2273Ser (c.6819A>C) in the general population?

FREM2 p.Arg2273Ser (c.6819A>C) is very rare (popmax 0.00695%, nfe) (gnomAD).

What do computational predictors say about FREM2 p.Arg2273Ser (c.6819A>C)?

AlphaMissense predicts likely benign (score 0.1479) — an in-silico prediction, not a clinical call.

FREM2 p.Arg2273Ser

c.6819A>C · rs202205485 · VCV3253161

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1479 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00695%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

isolated cryptophthalmia

Computational evidence

Protein change
AlphaMissense	0.1479	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -2.9, phastCons 0.97
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	16.36	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00695% European (non-Finnish) · 82/1,179,772 alleles

Filtering AF 0.00571% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.00545% 88/1,613,686 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,496
European (non-Finnish)grpmax	0.00695%	14,387
African / African-American	0.00134%	74,886

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg2273Ser
Coding: c.6819A>C
MANE Select: NM_207361
dbSNP: rs202205485
Type: single nucleotide variant
Location: chr13:38851762 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 2273: the calx-beta 5 domain; a UniProt-annotated variant site (in cryptop)

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

Disease context

isolated cryptophthalmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Fraser syndrome 2

Similar variants

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
FREM2 p.Gln717Ter Likely pathogenic ★★ same condition
FREM2 p.Ala1659Thr Uncertain significance ★★ ⚠ same condition
FREM2 p.Ala1664Val Uncertain significance ★★ ⚠ 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-arg2273ser (accessed [today's date]).

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