Is FH p.Val240Phe (c.718G>T) pathogenic?

FH p.Val240Phe (c.718G>T) is classified Conflicting classifications of pathogenicity in FH (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-02). AlphaMissense: likely pathogenic (0.9631); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Val240Phe (c.718G>T)?

FH p.Val240Phe (c.718G>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is FH p.Val240Phe (c.718G>T) in the general population?

FH p.Val240Phe (c.718G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FH p.Val240Phe (c.718G>T)?

AlphaMissense predicts likely pathogenic (score 0.9631) — an in-silico prediction, not a clinical call.

FH p.Val240Phe

c.718G>T · rs1291740270 · VCV1757591

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9631 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9631	likely pathogenic
REVEL	0.913	moderately pathogenic-leaning
SaProt	LLR -14.45	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 2.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 16 kb · p 7.5e-09 · regional, not allelic
Overall
CADD	29.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FH
Protein: p.Val240Phe
Coding: c.718G>T
MANE Select: NM_000143
dbSNP: rs1291740270
Type: single nucleotide variant
Location: chr1:241508623 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 240: a β-strand

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

Similar variants

FH p.Val240Leu Uncertain significance ★★ ⚠ same residue
FH p.Val240= Likely benign ★★ same residue
FH p.Val240Ile 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
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-val240phe (accessed [today's date]).

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