Is FIG4 p.Val12Ala (c.35T>C) pathogenic?

FIG4 p.Val12Ala (c.35T>C) is classified Uncertain significance in FIG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-13). AlphaMissense: likely pathogenic (0.6239); Very rare (popmax 0.00177%, amr); Associated with Inborn genetic diseases.

What condition is associated with FIG4 p.Val12Ala (c.35T>C)?

FIG4 p.Val12Ala (c.35T>C) is associated with Inborn genetic diseases (ClinVar).

How common is FIG4 p.Val12Ala (c.35T>C) in the general population?

FIG4 p.Val12Ala (c.35T>C) is very rare (popmax 0.00177%, amr) (gnomAD).

What do computational predictors say about FIG4 p.Val12Ala (c.35T>C)?

AlphaMissense predicts likely pathogenic (score 0.6239) — an in-silico prediction, not a clinical call.

FIG4 p.Val12Ala

c.35T>C · rs1583611553 · VCV1733082

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6239 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00177%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6239	likely pathogenic
REVEL	0.216	benign-leaning
SaProt	LLR -9.40	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.42 · regional, not allelic
Overall
CADD	23.9	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 0.00177% Admixed American · 1/56,478 alleles

Overall 6.3e-05% 1/1,586,896 alleles · very rare exomes 1/1,434,682 · genomes 0/152,214 · joint denominator

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: FIG4
Protein: p.Val12Ala
Coding: c.35T>C
MANE Select: NM_014845
dbSNP: rs1583611553
Type: single nucleotide variant
Location: chr6:109691470 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.65 · 1 PDB

Full FIG4 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

FIG4 c.2459+1G>A Pathogenic ★★ same condition
FIG4 p.Arg381Ter Pathogenic ★★ same condition
FIG4 p.Gln198Ter Pathogenic/Likely pathogenic ★★ same condition
FIG4 p.Leu643Ter Pathogenic ★★ same condition
FIG4 p.Trp246Ter Pathogenic ★★ same condition
FIG4 p.Tyr177Ter Pathogenic ★★ same condition
FIG4 c.2376+4C>T Uncertain significance ★★ same condition
FIG4 p.Ala308Val 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/fig4-p-val12ala (accessed [today's date]).

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