Is FHIT p.Arg46His (c.137G>A) pathogenic?

FHIT p.Arg46His (c.137G>A) is classified Uncertain significance in FHIT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-17). AlphaMissense: likely benign (0.2535); Very rare (popmax 0.00549%, sas).

How common is FHIT p.Arg46His (c.137G>A) in the general population?

FHIT p.Arg46His (c.137G>A) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about FHIT p.Arg46His (c.137G>A)?

AlphaMissense predicts likely benign (score 0.2535) — an in-silico prediction, not a clinical call.

FHIT p.Arg46His

c.137G>A · rs575922146 · VCV2326330

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2535 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2535	likely benign
REVEL	0.64	indeterminate
SaProt	LLR -8.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 785 kb · p 1.9e-05 · regional, not allelic
Overall
CADD	25.0	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 0.00549% South Asian · 5/91,084 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00242% 39/1,614,034 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,217
African / African-American	0.00533%	18,756
Admixed American	0.005%	20,007
East Asian	0.00223%	44,840
European (non-Finnish)	0.00212%	47,198
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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.Arg46His
Coding: c.137G>A
MANE Select: NM_002012
dbSNP: rs575922146
Type: single nucleotide variant
Location: chr3:60014119 (GRCh38)
Gene constraint: LOEUF 1.57 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 95.15 · 9 PDB
Residue 46: the hit domain

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

Similar variants

FHIT p.Arg46Cys Uncertain significance ★ ⚠ same residue
FHIT p.Ala127Asp Uncertain significance ★ ⚠ same type
FHIT p.Ala141Ser Uncertain significance ★ ⚠ same type
FHIT p.Ala24Pro 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
FHIT p.Glu138Lys 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-arg46his (accessed [today's date]).

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