Is FHIT p.Ser2= (c.6G>T) pathogenic?

FHIT p.Ser2= (c.6G>T) is classified Benign in FHIT (ClinVar, Single submitter, 2 submitters; last evaluated 2018-08-13). Rare (popmax 0.297%, nfe).

How common is FHIT p.Ser2= (c.6G>T) in the general population?

FHIT p.Ser2= (c.6G>T) is rare (popmax 0.297%, nfe) (gnomAD).

FHIT p.Ser2=

c.6G>T · rs137953369 · VCV708320

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.297%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.9	GERP -4.3
Overall
CADD	0.039	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.297% European (non-Finnish) · 3,503/1,177,810 alleles

Filtering AF 0.289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.286%

Overall 0.396% 6,371/1,608,544 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	3.88%	26
Remaining individualsnot grpmax-eligible	0.392%	255
European (non-Finnish)grpmax	0.297%	336
Amishnot grpmax-eligible	0.219%	456
Admixed American	0.117%	858
Middle Eastern	0.0664%	1,507
South Asian	0.0457%	2,189
African / African-American	0.0442%	2,264
Ashkenazi Jewishnot grpmax-eligible	0.0034%	29,404

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser2=
Coding: c.6G>T
MANE Select: NM_002012
dbSNP: rs137953369
Type: single nucleotide variant
Location: chr3:60536957 (GRCh38)
Gene constraint: LOEUF 1.57 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 95.15 · 9 PDB
Residue 2: 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-ser2 (accessed [today's date]).

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