Is FH p.Ala472Val (c.1415C>T) pathogenic?

FH p.Ala472Val (c.1415C>T) is classified Uncertain significance in FH (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-29). AlphaMissense: likely pathogenic (0.9498); Ultra-rare (popmax 0.0331%, mid); Associated with fumaric aciduria.

What condition is associated with FH p.Ala472Val (c.1415C>T)?

FH p.Ala472Val (c.1415C>T) is associated with fumaric aciduria, hereditary neoplastic syndrome (ClinVar).

How common is FH p.Ala472Val (c.1415C>T) in the general population?

FH p.Ala472Val (c.1415C>T) is ultra-rare (popmax 0.0331%, mid) (gnomAD).

How is Fumaric aciduria inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FH p.Ala472Val (c.1415C>T)?

AlphaMissense predicts likely pathogenic (score 0.9498) — an in-silico prediction, not a clinical call.

FH p.Ala472Val

c.1415C>T · rs765643179 · VCV662328

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9498 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

fumaric aciduria

Computational evidence

Protein change
AlphaMissense	0.9498	likely pathogenic
REVEL	0.935	strongly pathogenic-leaning
SaProt	LLR -14.15	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 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 16 kb · p 7.5e-09 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0331% Middle Eastern · 2/6,048 alleles

Filtering AF 0.00583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000558% 9/1,613,974 alleles · ultra-rare exomes 9/1,461,714 · genomes 0/152,260 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0331%	3,024
Remaining individualsnot grpmax-eligible	0.0048%	20,832
Admixed American	0.00167%	59,990
European (non-Finnish)	0.000254%	393,318

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.Ala472Val
Coding: c.1415C>T
MANE Select: NM_000143
dbSNP: rs765643179
Type: single nucleotide variant
Location: chr1:241497946 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 472: an α-helix

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

Disease context

fumaric aciduria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Fumaric aciduria (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

FH p.Ala472Thr Uncertain significance ★★ ⚠ same residue
FH p.Ala472= Likely benign ★★ same residue
FH p.Ala472fs Pathogenic ★ same residue
FH p.Ala472Asp 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-ala472val (accessed [today's date]).

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