Is FH p.Ile201Val (c.601A>G) pathogenic?

FH p.Ile201Val (c.601A>G) is classified Conflicting classifications of pathogenicity in FH (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-22). AlphaMissense: likely benign (0.0528); Very rare (popmax 0.000339%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Ile201Val (c.601A>G)?

FH p.Ile201Val (c.601A>G) is associated with hereditary neoplastic syndrome, fumaric aciduria (ClinVar).

How common is FH p.Ile201Val (c.601A>G) in the general population?

FH p.Ile201Val (c.601A>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about FH p.Ile201Val (c.601A>G)?

AlphaMissense predicts likely benign (score 0.0528) — an in-silico prediction, not a clinical call.

FH p.Ile201Val

c.601A>G · rs1659997422 · VCV1026405

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0528 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0528	likely benign
REVEL	0.242	benign-leaning
SaProt	LLR -6.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP -5.7
Regional constraint	o/e 0.75	unconstrained · MANE · 16 kb · p 7.5e-09 · regional, not allelic
Overall
CADD	0.002	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 0.000339% European (non-Finnish) · 4/1,179,864 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,928 alleles · very rare exomes 4/1,461,628 · genomes 0/152,300 · 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.Ile201Val
Coding: c.601A>G
MANE Select: NM_000143
dbSNP: rs1659997422
Type: single nucleotide variant
Location: chr1:241508740 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 201: 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.Ile201Met Uncertain significance ★★ ⚠ same residue
FH p.Ile201Thr Uncertain significance ★★ ⚠ same residue
FH p.Ile201= 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

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-ile201val (accessed [today's date]).

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