Is FH p.Ala20Ser (c.58G>T) pathogenic?

FH p.Ala20Ser (c.58G>T) is classified Conflicting classifications of pathogenicity in FH (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-02). AlphaMissense: likely benign (0.0913); Ultra-rare (popmax 0.0228%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Ala20Ser (c.58G>T)?

FH p.Ala20Ser (c.58G>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is FH p.Ala20Ser (c.58G>T) in the general population?

FH p.Ala20Ser (c.58G>T) is ultra-rare (popmax 0.0228%, mid) (gnomAD).

What do computational predictors say about FH p.Ala20Ser (c.58G>T)?

AlphaMissense predicts likely benign (score 0.0913) — an in-silico prediction, not a clinical call.

FH p.Ala20Ser

c.58G>T · rs572324497 · VCV2158854

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0913 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0228%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0913	likely benign
REVEL	0.365	indeterminate
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.98	GERP -2.7, phastCons 0.089
Regional constraint	o/e 1.12	unconstrained · MANE · 6,014 bp · p 0.17 · regional, not allelic
Overall
CADD	1.574	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 0.0228% Middle Eastern · 1/4,380 alleles

Overall 6.46e-05% 1/1,547,724 alleles · ultra-rare exomes 1/1,395,374 · genomes 0/152,350 · 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.Ala20Ser
Coding: c.58G>T
MANE Select: NM_000143
dbSNP: rs572324497
Type: single nucleotide variant
Location: chr1:241519665 (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.Ala20Pro Uncertain significance ★★ ⚠ same residue
FH p.Ala20Thr Uncertain significance ★★ ⚠ same residue
FH p.Ala20Val Uncertain significance ★★ ⚠ same residue
FH p.Ala20= Benign/Likely benign ★★ same residue
FH p.Ala20Gly 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

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-ala20ser (accessed [today's date]).

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