Is SDHC p.Arg133Pro (c.398G>C) pathogenic?

SDHC p.Arg133Pro (c.398G>C) is classified Uncertain significance in SDHC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-20). AlphaMissense: likely pathogenic (0.9854); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with SDHC p.Arg133Pro (c.398G>C)?

SDHC p.Arg133Pro (c.398G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is SDHC p.Arg133Pro (c.398G>C) in the general population?

SDHC p.Arg133Pro (c.398G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SDHC p.Arg133Pro (c.398G>C)?

AlphaMissense predicts likely pathogenic (score 0.9854) — an in-silico prediction, not a clinical call.

SDHC p.Arg133Pro

c.398G>C · VCV4072689

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9854 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9854	likely pathogenic · top 1% in SDHC
REVEL	0.962	strongly pathogenic-leaning
SaProt	LLR -15.66	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 22 kb · p 1.5e-06 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: SDHC
Protein: p.Arg133Pro
Coding: c.398G>C
MANE Select: NM_003001
Type: single nucleotide variant
Location: chr1:161356833 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 91.05 · 2 PDB
Residue 133: an α-helix

Full SDHC 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

SDHC p.Arg133Ter Pathogenic ★★ same residue
SDHC p.Arg133Gln Uncertain significance ★★ ⚠ same residue
SDHC p.Arg133= Likely benign ★ same residue
SDHC c.179+1G>C Likely pathogenic ★★ same condition
SDHC c.180-2A>G Likely pathogenic ★★ same condition
SDHC c.21-2A>G Pathogenic/Likely pathogenic ★★ same condition
SDHC c.241+1G>A Likely pathogenic ★★ same condition
SDHC c.405+1G>A 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/sdhc-p-arg133pro (accessed [today's date]).

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