Is FREM2 p.Ala202Pro (c.604G>C) pathogenic?

FREM2 p.Ala202Pro (c.604G>C) is classified Uncertain significance in FREM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-10). AlphaMissense: likely benign (0.1227); Absent from gnomAD v4.1.

How common is FREM2 p.Ala202Pro (c.604G>C) in the general population?

FREM2 p.Ala202Pro (c.604G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FREM2 p.Ala202Pro (c.604G>C)?

AlphaMissense predicts likely benign (score 0.1227) — an in-silico prediction, not a clinical call.

FREM2 p.Ala202Pro

c.604G>C · rs2541349556 · VCV2807367

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1227 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1227	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -7.30	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 2.3	GERP -2.9, phastCons 0.074
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	17.2	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

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.Ala202Pro
Coding: c.604G>C
MANE Select: NM_207361
dbSNP: rs2541349556
Type: single nucleotide variant
Location: chr13:38687948 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)

Full FREM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FREM2 p.Ala202= Likely benign ★ same residue
FREM2 c.5263+1G>A Likely pathogenic ★★ same type
FREM2 c.6925+1G>T Likely pathogenic ★★ same type
FREM2 p.Arg1355Ter Pathogenic/Likely pathogenic ★★ same type
FREM2 p.Arg2243Ter Pathogenic/Likely pathogenic ★★ same type
FREM2 p.Arg638Ter Likely pathogenic ★★ same type
FREM2 p.Arg736Ter Pathogenic ★★ same type
FREM2 p.Arg809Ter Pathogenic ★★ same type

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-ala202pro (accessed [today's date]).

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