Is FREM2 p.Thr1111Pro (c.3331A>C) pathogenic?

FREM2 p.Thr1111Pro (c.3331A>C) is classified Uncertain significance in FREM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-17). AlphaMissense: likely benign (0.1114); Absent from gnomAD v4.1; Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Thr1111Pro (c.3331A>C)?

FREM2 p.Thr1111Pro (c.3331A>C) is associated with Fraser syndrome 2, isolated cryptophthalmia (ClinVar).

How common is FREM2 p.Thr1111Pro (c.3331A>C) in the general population?

FREM2 p.Thr1111Pro (c.3331A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FREM2 p.Thr1111Pro (c.3331A>C)?

AlphaMissense predicts likely benign (score 0.1114) — an in-silico prediction, not a clinical call.

FREM2 p.Thr1111Pro

c.3331A>C · VCV3576054

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1114 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Fraser syndrome 2

Computational evidence

Protein change
AlphaMissense	0.1114	likely benign
REVEL	0.149	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 1.4	GERP -0.56
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	16.64	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

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.Thr1111Pro
Coding: c.3331A>C
MANE Select: NM_207361
Type: single nucleotide variant
Location: chr13:38690675 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 1111: 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.Thr1111Ala Uncertain significance ★ ⚠ 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-thr1111pro (accessed [today's date]).

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