Is FH p.Ala217Val (c.650C>T) pathogenic?

FH p.Ala217Val (c.650C>T) is classified Uncertain significance in FH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-10). AlphaMissense: likely benign (0.1961); Absent from gnomAD v4.1.

How common is FH p.Ala217Val (c.650C>T) in the general population?

FH p.Ala217Val (c.650C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FH p.Ala217Val (c.650C>T)?

AlphaMissense predicts likely benign (score 0.1961) — an in-silico prediction, not a clinical call.

FH p.Ala217Val

c.650C>T · rs2147919565 · VCV2571738

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1961 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1961	likely benign
REVEL	0.687	pathogenic-leaning
SaProt	LLR -10.68	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 16 kb · p 7.5e-09 · regional, not allelic
Overall
CADD	23.3	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.Ala217Val
Coding: c.650C>T
MANE Select: NM_000143
dbSNP: rs2147919565
Type: single nucleotide variant
Location: chr1:241508691 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 217: an α-helix

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

Similar variants

FH p.Ala217Ser Uncertain significance ★ ⚠ same residue
FH p.Ala217= Likely benign ★ same residue
FH c.1108+1G>A Pathogenic ★★ same type
FH c.1108+1G>T Pathogenic/Likely pathogenic ★★ same type
FH c.1236+1G>A Pathogenic/Likely pathogenic ★★ same type
FH c.1236+1G>C Pathogenic ★★ same type
FH c.1236+2T>G Pathogenic ★★ same type
FH c.1237-1G>T Likely pathogenic ★★ same type

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-ala217val (accessed [today's date]).

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