Is FH p.Ala25= (c.75T>G) pathogenic?

FH p.Ala25= (c.75T>G) is classified Likely benign in FH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-05). Very rare (popmax 0.000174%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Ala25= (c.75T>G)?

FH p.Ala25= (c.75T>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is FH p.Ala25= (c.75T>G) in the general population?

FH p.Ala25= (c.75T>G) is very rare (popmax 0.000174%, nfe) (gnomAD).

FH p.Ala25=

c.75T>G · rs2147926948 · VCV2452778

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000174%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.57	GERP 1.5, phastCons 0.001
Overall
CADD	7.319	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000174% European (non-Finnish) · 2/1,146,508 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000129% 2/1,548,014 alleles · very rare exomes 2/1,395,686 · genomes 0/152,328 · 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.Ala25=
Coding: c.75T>G
MANE Select: NM_000143
dbSNP: rs2147926948
Type: single nucleotide variant
Location: chr1:241519648 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB

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.Ala25Pro Uncertain significance ★★ ⚠ same residue
FH p.Ala25Thr Uncertain significance ★★ ⚠ same residue
FH p.Ala25Val Uncertain significance ★★ ⚠ same residue
FH p.Ala25Asp 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

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-ala25 (accessed [today's date]).

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