Is SDHC p.Ala2Asp (c.5C>A) pathogenic?

SDHC p.Ala2Asp (c.5C>A) is classified Uncertain significance in SDHC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-24). AlphaMissense: ambiguous (0.5047); Absent from gnomAD v4.1; Associated with pheochromocytoma/paraganglioma syndrome 3.

What condition is associated with SDHC p.Ala2Asp (c.5C>A)?

SDHC p.Ala2Asp (c.5C>A) is associated with pheochromocytoma/paraganglioma syndrome 3, gastrointestinal stromal tumor (ClinVar).

How common is SDHC p.Ala2Asp (c.5C>A) in the general population?

SDHC p.Ala2Asp (c.5C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SDHC p.Ala2Asp (c.5C>A)?

AlphaMissense predicts ambiguous (score 0.5047) — an in-silico prediction, not a clinical call.

SDHC p.Ala2Asp

c.5C>A · VCV4787127

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5047 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

pheochromocytoma/paraganglioma syndrome 3

Computational evidence

Protein change
AlphaMissense	0.5047	ambiguous
REVEL	0.602	indeterminate
SaProt	LLR -10.80	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.4	GERP 1.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 26 kb · p 0.78 · regional, not allelic
Overall
CADD	25.5	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

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.Ala2Asp
Coding: c.5C>A
MANE Select: NM_003001
Type: single nucleotide variant
Location: chr1:161314410 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 91.05 · 2 PDB

Full SDHC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pheochromocytoma/paraganglioma syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: gastrointestinal stromal tumor

Similar variants

SDHC p.Ala2Gly Uncertain significance ★★ ⚠ same residue
SDHC p.Ala2Pro Uncertain significance ★★ ⚠ same residue
SDHC p.Ala2Ser Uncertain significance ★★ ⚠ same residue
SDHC p.Ala2Thr Uncertain significance ★★ ⚠ same residue
SDHC p.Ala2Val Uncertain significance ★★ same residue
SDHC p.Ala2= Benign/Likely benign ★★ same residue
SDHC c.179+1G>C Likely pathogenic ★★ same condition
SDHC c.179+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/sdhc-p-ala2asp (accessed [today's date]).

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