Is FH p.Ala486= (c.1458T>C) pathogenic?

FH p.Ala486= (c.1458T>C) is classified Benign/Likely benign in FH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-01). Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Ala486= (c.1458T>C)?

FH p.Ala486= (c.1458T>C) is associated with hereditary neoplastic syndrome, hereditary leiomyomatosis and renal cell cancer (ClinVar).

How common is FH p.Ala486= (c.1458T>C) in the general population?

FH p.Ala486= (c.1458T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

FH p.Ala486=

c.1458T>C · rs771879458 · VCV1773094

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -5.6
Overall
CADD	1.935	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,048 alleles

Overall 6.2e-05% 1/1,613,790 alleles · very rare exomes 1/1,461,476 · genomes 0/152,314 · 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.Ala486=
Coding: c.1458T>C
MANE Select: NM_000143
dbSNP: rs771879458
Type: single nucleotide variant
Location: chr1:241497903 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 486: 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

Similar variants

FH p.Ala486Asp Pathogenic ★ same residue
FH p.Ala486Thr Uncertain significance ★ ⚠ 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
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-ala486 (accessed [today's date]).

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