Is FH p.Ala117Pro (c.349G>C) pathogenic?

FH p.Ala117Pro (c.349G>C) is classified Pathogenic/Likely pathogenic in FH (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-01). AlphaMissense: likely pathogenic (0.9735); Very rare (popmax 0.000424%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Ala117Pro (c.349G>C)?

FH p.Ala117Pro (c.349G>C) is associated with hereditary neoplastic syndrome, hereditary leiomyomatosis and renal cell cancer (ClinVar).

How common is FH p.Ala117Pro (c.349G>C) in the general population?

FH p.Ala117Pro (c.349G>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about FH p.Ala117Pro (c.349G>C)?

AlphaMissense predicts likely pathogenic (score 0.9735) — an in-silico prediction, not a clinical call.

FH p.Ala117Pro

c.349G>C · rs886039363 · VCV265146

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9735 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9735	likely pathogenic ✓ concordant with ClinVar
REVEL	0.885	moderately pathogenic-leaning
SaProt	LLR -15.70	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 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 16 kb · p 7.5e-09 · regional, not allelic
Overall
CADD	26.9	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 0.000424% European (non-Finnish) · 5/1,179,946 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,052 alleles · very rare exomes 5/1,461,762 · genomes 0/152,290 · joint denominator

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.Ala117Pro
Coding: c.349G>C
MANE Select: NM_000143
dbSNP: rs886039363
Type: single nucleotide variant
Location: chr1:241513632 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 117: a UniProt-annotated variant site (in hlrcc); 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

Also linked: hereditary leiomyomatosis and renal cell cancer

Similar variants

FH p.Ala117= Likely benign ★ same residue
FH c.1108+1G>A Pathogenic ★★ same condition
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

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-ala117pro (accessed [today's date]).

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