Is SDHC p.Ala3Pro (c.7G>C) pathogenic?

SDHC p.Ala3Pro (c.7G>C) is classified Uncertain significance in SDHC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-21). AlphaMissense: likely benign (0.261); Very rare (popmax 0.0011%, sas); Associated with gastrointestinal stromal tumor.

What condition is associated with SDHC p.Ala3Pro (c.7G>C)?

SDHC p.Ala3Pro (c.7G>C) is associated with gastrointestinal stromal tumor, pheochromocytoma/paraganglioma syndrome 3, hereditary neoplastic syndrome (ClinVar).

How common is SDHC p.Ala3Pro (c.7G>C) in the general population?

SDHC p.Ala3Pro (c.7G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Gastrointestinal stromal tumor inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SDHC p.Ala3Pro (c.7G>C)?

AlphaMissense predicts likely benign (score 0.261) — an in-silico prediction, not a clinical call.

SDHC p.Ala3Pro

c.7G>C · rs748243732 · VCV2946953

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.261 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

gastrointestinal stromal tumor

Computational evidence

Protein change
AlphaMissense	0.261	likely benign
REVEL	0.614	indeterminate
SaProt	LLR -10.92	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.44, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 26 kb · p 0.78 · regional, not allelic
Overall
CADD	24.5	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

Grpmax group 0.0011% South Asian · 1/91,018 alleles

Overall 6.2e-05% 1/1,613,406 alleles · very rare exomes 1/1,461,868 · genomes 0/151,538 · 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: SDHC
Protein: p.Ala3Pro
Coding: c.7G>C
MANE Select: NM_003001
dbSNP: rs748243732
Type: single nucleotide variant
Location: chr1:161314412 (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

gastrointestinal stromal tumor — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma/paraganglioma syndrome 3 hereditary neoplastic syndrome

For Gastrointestinal stromal tumor (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

SDHC p.Ala3Glu Uncertain significance ★★ same residue
SDHC p.Ala3Ser Uncertain significance ★★ ⚠ same residue
SDHC p.Ala3Thr Uncertain significance ★★ ⚠ same residue
SDHC p.Ala3Val Uncertain significance ★★ ⚠ same residue
SDHC p.Ala3= Benign/Likely benign ★★ same residue
SDHC p.Ala3fs Pathogenic ★ 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-ala3pro (accessed [today's date]).

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