Is FH p.Val73Met (c.217G>A) pathogenic?

FH p.Val73Met (c.217G>A) is classified Conflicting classifications of pathogenicity in FH (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1914); Ultra-rare (popmax 0.0203%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Val73Met (c.217G>A)?

FH p.Val73Met (c.217G>A) is associated with hereditary neoplastic syndrome, hereditary leiomyomatosis and renal cell cancer, fumaric aciduria (ClinVar).

How common is FH p.Val73Met (c.217G>A) in the general population?

FH p.Val73Met (c.217G>A) is ultra-rare (popmax 0.0203%, nfe) (gnomAD).

What do computational predictors say about FH p.Val73Met (c.217G>A)?

AlphaMissense predicts likely benign (score 0.1914) — an in-silico prediction, not a clinical call.

FH p.Val73Met

c.217G>A · rs201878591 · VCV184137

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.1914 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0203%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1914	likely benign
REVEL	0.615	indeterminate
SaProt	LLR -9.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 6,014 bp · p 0.17 · regional, not allelic
Overall
CADD	23.0	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 0.0203% European (non-Finnish) · 239/1,180,024 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0173%

Overall 0.0159% 257/1,614,132 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0203%	4,937
African / African-American	0.012%	8,337
East Asian	0.00669%	14,959
Remaining individualsnot grpmax-eligible	0.0064%	15,626
Admixed American	0.00333%	30,016

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.Val73Met
Coding: c.217G>A
MANE Select: NM_000143
dbSNP: rs201878591
Type: single nucleotide variant
Location: chr1:241517232 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 73: 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 fumaric aciduria

Similar variants

FH p.Val73Ala Uncertain significance ★★ same residue
FH p.Val73Leu Uncertain significance ★★ ⚠ same residue
FH p.Val73= Conflicting classifications of pathogenicity ★ 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

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-val73met (accessed [today's date]).

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