Is FREM2 p.Pro1553Ala (c.4657C>G) pathogenic?

FREM2 p.Pro1553Ala (c.4657C>G) is classified Conflicting classifications of pathogenicity in FREM2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.2786); Rare (popmax 0.163%, eas); Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Pro1553Ala (c.4657C>G)?

FREM2 p.Pro1553Ala (c.4657C>G) is associated with Fraser syndrome 2, microcephaly, isolated cryptophthalmia (ClinVar).

How common is FREM2 p.Pro1553Ala (c.4657C>G) in the general population?

FREM2 p.Pro1553Ala (c.4657C>G) is rare (popmax 0.163%, eas) (gnomAD).

What do computational predictors say about FREM2 p.Pro1553Ala (c.4657C>G)?

AlphaMissense predicts likely benign (score 0.2786) — an in-silico prediction, not a clinical call.

FREM2 p.Pro1553Ala

c.4657C>G · rs184635412 · VCV311979

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2786 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.163%, eas)

Conditions

Fraser syndrome 2

Computational evidence

Protein change
AlphaMissense	0.2786	likely benign
REVEL	0.447	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	22.2	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 0.163% East Asian · 73/44,888 alleles

Filtering AF 0.133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.122%

Overall 0.00477% 77/1,614,240 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.163%	615
Remaining individualsnot grpmax-eligible	0.0064%	15,628

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.Pro1553Ala
Coding: c.4657C>G
MANE Select: NM_207361
dbSNP: rs184635412
Type: single nucleotide variant
Location: chr13:38692001 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 1553: 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: microcephaly isolated cryptophthalmia

Similar variants

FREM2 p.Pro1553= 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-pro1553ala (accessed [today's date]).

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