Is FH p.Thr331Ala (c.991A>G) pathogenic?

FH p.Thr331Ala (c.991A>G) is classified Uncertain significance in FH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-14). AlphaMissense: likely benign (0.0621); Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Thr331Ala (c.991A>G)?

FH p.Thr331Ala (c.991A>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is FH p.Thr331Ala (c.991A>G) in the general population?

FH p.Thr331Ala (c.991A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about FH p.Thr331Ala (c.991A>G)?

AlphaMissense predicts likely benign (score 0.0621) — an in-silico prediction, not a clinical call.

FH p.Thr331Ala

c.991A>G · rs1459131048 · VCV1385346

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0621 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0621	likely benign
REVEL	0.329	indeterminate
SaProt	LLR -4.06	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.16	GERP -4.4, phastCons 0.015
Regional constraint	o/e 0.75	unconstrained · MANE · 16 kb · p 7.5e-09 · regional, not allelic
Overall
CADD	16.64	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 0.00167% Admixed American · 1/60,020 alleles

Overall 0.000124% 2/1,614,152 alleles · very rare exomes 2/1,461,852 · genomes 0/152,300 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,020
Remaining individualsnot grpmax-eligible	0.0016%	62,506

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: FH
Protein: p.Thr331Ala
Coding: c.991A>G
MANE Select: NM_000143
dbSNP: rs1459131048
Type: single nucleotide variant
Location: chr1:241504159 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 331: an α-helix

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FH p.Thr331= Benign/Likely benign ★★ same residue
FH c.1108+1G>T Pathogenic/Likely pathogenic ★★ same condition
FH c.1236+1G>A Pathogenic/Likely pathogenic ★★ same condition
FH c.1236+1G>C Pathogenic ★★ same condition
FH c.1236+2T>G Pathogenic ★★ same condition
FH c.1237-1G>T Likely pathogenic ★★ same condition
FH c.1390+1G>T Pathogenic/Likely pathogenic ★★ same condition
FH c.1391-1G>C Pathogenic ★★ 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/fh-p-thr331ala (accessed [today's date]).

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