Is FREM2 p.Pro1903Ala (c.5707C>G) pathogenic?

FREM2 p.Pro1903Ala (c.5707C>G) is classified Uncertain significance in FREM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.1365); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with FREM2 p.Pro1903Ala (c.5707C>G)?

FREM2 p.Pro1903Ala (c.5707C>G) is associated with Inborn genetic diseases (ClinVar).

How common is FREM2 p.Pro1903Ala (c.5707C>G) in the general population?

FREM2 p.Pro1903Ala (c.5707C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FREM2 p.Pro1903Ala (c.5707C>G)?

AlphaMissense predicts likely benign (score 0.1365) — an in-silico prediction, not a clinical call.

FREM2 p.Pro1903Ala

c.5707C>G · VCV4620351

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1365 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1365	likely benign
REVEL	0.538	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	24.5	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.Pro1903Ala
Coding: c.5707C>G
MANE Select: NM_207361
Type: single nucleotide variant
Location: chr13:38783135 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 1903: the calx-beta 2 domain; a UniProt-annotated variant site (in cryptop)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FREM2 p.Ala1029Val Uncertain significance ★★ ⚠ same condition
FREM2 p.Ala565Gly Uncertain significance ★★ same condition
FREM2 p.Ala61Pro Uncertain significance ★★ ⚠ same condition
FREM2 p.Arg1166Cys Uncertain significance ★★ ⚠ same condition
FREM2 p.Arg1523Cys Uncertain significance ★★ same condition
FREM2 p.Arg156Leu Uncertain significance ★★ ⚠ same condition
FREM2 p.Arg1765Cys Uncertain significance ★★ ⚠ same condition
FREM2 p.Arg1765His 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-pro1903ala (accessed [today's date]).

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