Is FH p.Arg12Ser (c.34C>A) pathogenic?

FH p.Arg12Ser (c.34C>A) is classified Uncertain significance in FH (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-11). AlphaMissense: likely benign (0.1975); Absent from gnomAD v4.1.

How common is FH p.Arg12Ser (c.34C>A) in the general population?

FH p.Arg12Ser (c.34C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FH p.Arg12Ser (c.34C>A)?

AlphaMissense predicts likely benign (score 0.1975) — an in-silico prediction, not a clinical call.

FH p.Arg12Ser

c.34C>A · rs199912971 · VCV1483541

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1975 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1975	likely benign
REVEL	0.458	indeterminate
SaProt	LLR -5.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.48	GERP -3.8
Regional constraint	o/e 1.12	unconstrained · MANE · 6,014 bp · p 0.17 · regional, not allelic
Overall
CADD	7.36	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Arg12Ser
Coding: c.34C>A
MANE Select: NM_000143
dbSNP: rs199912971
Type: single nucleotide variant
Location: chr1:241519689 (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

Similar variants

FH p.Arg12Cys Uncertain significance ★★ same residue
FH p.Arg12Gly Uncertain significance ★★ ⚠ same residue
FH p.Arg12His Uncertain significance ★★ ⚠ same residue
FH p.Arg12= Likely benign ★★ same residue
FH p.Arg12Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
FH p.Arg12Pro Uncertain significance ★ ⚠ same residue
FH c.1108+1G>A Pathogenic ★★ same type
FH c.1108+1G>T Pathogenic/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-arg12ser (accessed [today's date]).

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