Is FREM2 p.Pro398Ala (c.1192C>G) pathogenic?

FREM2 p.Pro398Ala (c.1192C>G) is classified Uncertain significance in FREM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-31). AlphaMissense: likely benign (0.2646); Very rare (popmax 0.00695%, nfe); Associated with isolated cryptophthalmia.

What condition is associated with FREM2 p.Pro398Ala (c.1192C>G)?

FREM2 p.Pro398Ala (c.1192C>G) is associated with isolated cryptophthalmia, Fraser syndrome 2 (ClinVar).

How common is FREM2 p.Pro398Ala (c.1192C>G) in the general population?

FREM2 p.Pro398Ala (c.1192C>G) is very rare (popmax 0.00695%, nfe) (gnomAD).

What do computational predictors say about FREM2 p.Pro398Ala (c.1192C>G)?

AlphaMissense predicts likely benign (score 0.2646) — an in-silico prediction, not a clinical call.

FREM2 p.Pro398Ala

c.1192C>G · rs372777373 · VCV1393442

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2646 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00695%, nfe)

Conditions

isolated cryptophthalmia

Computational evidence

Protein change
AlphaMissense	0.2646	likely benign
REVEL	0.395	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	21.0	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 0.00695% European (non-Finnish) · 82/1,179,938 alleles

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

Overall 0.00533% 86/1,613,840 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00695%	14,389
Remaining individualsnot grpmax-eligible	0.0064%	15,619

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.Pro398Ala
Coding: c.1192C>G
MANE Select: NM_207361
dbSNP: rs372777373
Type: single nucleotide variant
Location: chr13:38688536 (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

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

Also linked: Fraser syndrome 2

Similar variants

FREM2 p.Pro398His Uncertain significance ★ same residue
FREM2 p.Pro398Leu 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

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-pro398ala (accessed [today's date]).

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