Is FHIT p.Val31Ala (c.92T>C) pathogenic?

FHIT p.Val31Ala (c.92T>C) is classified Uncertain significance in FHIT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: ambiguous (0.5259); Very rare (popmax 0.00476%, nfe).

How common is FHIT p.Val31Ala (c.92T>C) in the general population?

FHIT p.Val31Ala (c.92T>C) is very rare (popmax 0.00476%, nfe) (gnomAD).

What do computational predictors say about FHIT p.Val31Ala (c.92T>C)?

AlphaMissense predicts ambiguous (score 0.5259) — an in-silico prediction, not a clinical call.

FHIT p.Val31Ala

c.92T>C · VCV4668647

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5259 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00476%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5259	ambiguous
REVEL	0.626	indeterminate
SaProt	LLR -11.50	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.2	GERP 2.1, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 785 kb · p 1.9e-05 · regional, not allelic
Overall
CADD	26.8	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 0.00476% European (non-Finnish) · 56/1,177,128 alleles

Filtering AF 0.00376% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00338%

Overall 0.00374% 60/1,605,544 alleles · very rare exomes 55/1,453,632 · genomes 5/151,912 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00476%	21,020
Remaining individualsnot grpmax-eligible	0.00322%	31,048
African / African-American	0.00135%	74,242
South Asian	0.00113%	88,790

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: FHIT
Protein: p.Val31Ala
Coding: c.92T>C
MANE Select: NM_002012
Type: single nucleotide variant
Location: chr3:60536871 (GRCh38)
Gene constraint: LOEUF 1.57 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 95.15 · 9 PDB
Residue 31: the hit domain

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

Similar variants

FHIT p.Ala127Asp Uncertain significance ★ ⚠ same type
FHIT p.Ala141Ser Uncertain significance ★ ⚠ same type
FHIT p.Ala24Pro Uncertain significance ★ ⚠ same type
FHIT p.Arg46Cys Uncertain significance ★ ⚠ same type
FHIT p.Arg46His Uncertain significance ★ ⚠ same type
FHIT p.Arg51His Uncertain significance ★ ⚠ same type
FHIT p.Asn110Ser Uncertain significance ★ ⚠ same type
FHIT p.Cys39Tyr Uncertain significance ★ ⚠ 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/fhit-p-val31ala (accessed [today's date]).

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