Is FHIT p.Pro101Ser (c.301C>T) pathogenic?

FHIT p.Pro101Ser (c.301C>T) is classified Likely benign in FHIT (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-12-28). AlphaMissense: likely pathogenic (0.9419); Rare (popmax 0.443%, sas); Associated with FHIT-related disorder.

What condition is associated with FHIT p.Pro101Ser (c.301C>T)?

FHIT p.Pro101Ser (c.301C>T) is associated with FHIT-related disorder (ClinVar).

How common is FHIT p.Pro101Ser (c.301C>T) in the general population?

FHIT p.Pro101Ser (c.301C>T) is rare (popmax 0.443%, sas) (gnomAD).

What do computational predictors say about FHIT p.Pro101Ser (c.301C>T)?

AlphaMissense predicts likely pathogenic (score 0.9419) — an in-silico prediction, not a clinical call.

FHIT p.Pro101Ser

c.301C>T · rs533270218 · VCV3049106

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9419 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.443%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FHIT-related disorder

Computational evidence

Protein change
AlphaMissense	0.9419	likely pathogenic
REVEL	0.943	strongly pathogenic-leaning
SaProt	LLR -14.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 785 kb · p 1.9e-05 · regional, not allelic
Overall
CADD	25.5	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 0.443% South Asian · 403/91,052 alleles

Filtering AF 0.407% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.393%

Overall 0.0275% 443/1,613,802 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.443%	226
Remaining individualsnot grpmax-eligible	0.048%	2,083
Middle Eastern	0.0165%	6,060
Admixed American	0.00167%	59,962
African / African-American	0.00133%	74,974
European (non-Finnish)	0.000593%	168,556

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.Pro101Ser
Coding: c.301C>T
MANE Select: NM_002012
dbSNP: rs533270218
Type: single nucleotide variant
Location: chr3:59922393 (GRCh38)
Gene constraint: LOEUF 1.57 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 95.15 · 9 PDB
Residue 101: the hit domain; a β-strand

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

Disease context

FHIT-related disorder

Similar variants

FHIT c.104-64T>C Likely benign same condition
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

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-pro101ser (accessed [today's date]).

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