Is FREM2 p.Val430Ala (c.1289T>C) pathogenic?

FREM2 p.Val430Ala (c.1289T>C) is classified Uncertain significance in FREM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-25). AlphaMissense: likely benign (0.3186); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with FREM2 p.Val430Ala (c.1289T>C)?

FREM2 p.Val430Ala (c.1289T>C) is associated with Inborn genetic diseases (ClinVar).

How common is FREM2 p.Val430Ala (c.1289T>C) in the general population?

FREM2 p.Val430Ala (c.1289T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about FREM2 p.Val430Ala (c.1289T>C)?

AlphaMissense predicts likely benign (score 0.3186) — an in-silico prediction, not a clinical call.

FREM2 p.Val430Ala

c.1289T>C · VCV4026681

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3186 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3186	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -8.12	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 5	GERP 2.7, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	23.7	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

Grpmax group 0.00223% East Asian · 1/44,870 alleles

Overall 0.000186% 3/1,614,156 alleles · very rare exomes 3/1,461,874 · genomes 0/152,282 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,870
Admixed American	0.00167%	60,016
European (non-Finnish)	8.47e-05%	1,180,018

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.Val430Ala
Coding: c.1289T>C
MANE Select: NM_207361
Type: single nucleotide variant
Location: chr13:38688633 (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

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

Similar variants

FREM2 p.Val430Met Uncertain significance ★★ same residue
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

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-val430ala (accessed [today's date]).

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