Is FREM2 p.Ser502Phe (c.1505C>T) pathogenic?

FREM2 p.Ser502Phe (c.1505C>T) is classified Uncertain significance in FREM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-28). AlphaMissense: likely benign (0.0908); Ultra-rare (popmax 0.0236%, nfe); Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Ser502Phe (c.1505C>T)?

FREM2 p.Ser502Phe (c.1505C>T) is associated with Fraser syndrome 2, isolated cryptophthalmia (ClinVar).

How common is FREM2 p.Ser502Phe (c.1505C>T) in the general population?

FREM2 p.Ser502Phe (c.1505C>T) is ultra-rare (popmax 0.0236%, nfe) (gnomAD).

What do computational predictors say about FREM2 p.Ser502Phe (c.1505C>T)?

AlphaMissense predicts likely benign (score 0.0908) — an in-silico prediction, not a clinical call.

FREM2 p.Ser502Phe

c.1505C>T · rs202008233 · VCV311947

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0908 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0236%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fraser syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0908	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -9.19	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.5, phastCons 0.45
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	18.88	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0236% European (non-Finnish) · 278/1,179,944 alleles

Filtering AF 0.0213% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0204%

Overall 0.0183% 296/1,613,594 alleles · ultra-rare exomes 267/1,461,428 · genomes 29/152,166 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0236%	4,244
Finnishnot grpmax-eligible	0.0157%	6,372
Remaining individualsnot grpmax-eligible	0.00961%	10,409
Admixed American	0.00167%	60,004
African / African-American	0.00133%	74,912

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.Ser502Phe
Coding: c.1505C>T
MANE Select: NM_207361
dbSNP: rs202008233
Type: single nucleotide variant
Location: chr13:38688849 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)

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.Ser502= 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
FREM2 p.Gln717Ter Likely pathogenic ★★ same condition
FREM2 p.Ala1659Thr 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-ser502phe (accessed [today's date]).

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