Is FH p.Ala70Val (c.209C>T) pathogenic?

FH p.Ala70Val (c.209C>T) is classified Uncertain significance in FH (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-03-04). AlphaMissense: likely pathogenic (0.9129); Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Ala70Val (c.209C>T)?

FH p.Ala70Val (c.209C>T) is associated with hereditary neoplastic syndrome, fumaric aciduria (ClinVar).

How common is FH p.Ala70Val (c.209C>T) in the general population?

FH p.Ala70Val (c.209C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about FH p.Ala70Val (c.209C>T)?

AlphaMissense predicts likely pathogenic (score 0.9129) — an in-silico prediction, not a clinical call.

FH p.Ala70Val

c.209C>T · rs1573888433 · VCV649267

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9129 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9129	likely pathogenic
REVEL	0.81	moderately pathogenic-leaning
SaProt	LLR -9.47	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 6,014 bp · p 0.17 · regional, not allelic
Overall
CADD	26.8	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 0.00133% African / African-American · 1/74,990 alleles

Overall 0.000124% 2/1,614,068 alleles · very rare exomes 2/1,461,860 · genomes 0/152,208 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,990
European (non-Finnish)	8.47e-05%	1,180,025

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.Ala70Val
Coding: c.209C>T
MANE Select: NM_000143
dbSNP: rs1573888433
Type: single nucleotide variant
Location: chr1:241517240 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 70: 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: fumaric aciduria

Similar variants

FH p.Ala70= Benign/Likely benign ★★ same residue
FH p.Ala70Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
FH p.Ala70Gly Uncertain significance ★ ⚠ same residue
FH p.Ala70Ser Uncertain significance ⚠ 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

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-ala70val (accessed [today's date]).

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