Is FREM2 p.Ser1168Phe (c.3503C>T) pathogenic?

FREM2 p.Ser1168Phe (c.3503C>T) is classified Uncertain significance in FREM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-05). AlphaMissense: likely pathogenic (0.6389); Absent from gnomAD v4.1; Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Ser1168Phe (c.3503C>T)?

FREM2 p.Ser1168Phe (c.3503C>T) is associated with Fraser syndrome 2, isolated cryptophthalmia (ClinVar).

How common is FREM2 p.Ser1168Phe (c.3503C>T) in the general population?

FREM2 p.Ser1168Phe (c.3503C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FREM2 p.Ser1168Phe (c.3503C>T)?

AlphaMissense predicts likely pathogenic (score 0.6389) — an in-silico prediction, not a clinical call.

FREM2 p.Ser1168Phe

c.3503C>T · VCV3576067

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6389 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Fraser syndrome 2

Computational evidence

Protein change
AlphaMissense	0.6389	likely pathogenic
REVEL	0.537	indeterminate
SaProt	—	not scored · why
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	26.2	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FREM2
Protein: p.Ser1168Phe
Coding: c.3503C>T
MANE Select: NM_207361
Type: single nucleotide variant
Location: chr13:38690847 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 1168: 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.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-ser1168phe (accessed [today's date]).

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