Is SDHC p.Ala2Val (c.5C>T) pathogenic?

SDHC p.Ala2Val (c.5C>T) is classified Uncertain significance in SDHC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-18). AlphaMissense: ambiguous (0.4285); Very rare (popmax 0.000169%, nfe); Associated with hereditary pheochromocytoma-paraganglioma.

What condition is associated with SDHC p.Ala2Val (c.5C>T)?

SDHC p.Ala2Val (c.5C>T) is associated with hereditary pheochromocytoma-paraganglioma, pheochromocytoma/paraganglioma syndrome 3, gastrointestinal stromal tumor (ClinVar).

How common is SDHC p.Ala2Val (c.5C>T) in the general population?

SDHC p.Ala2Val (c.5C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Hereditary pheochromocytoma-paraganglioma inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SDHC p.Ala2Val (c.5C>T)?

AlphaMissense predicts ambiguous (score 0.4285) — an in-silico prediction, not a clinical call.

SDHC p.Ala2Val

c.5C>T · rs781337432 · VCV2625945

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4285 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

hereditary pheochromocytoma-paraganglioma

Computational evidence

Protein change
AlphaMissense	0.4285	ambiguous
REVEL	0.641	indeterminate
SaProt	LLR -9.92	tolerated
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	26.5	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 0.000169% European (non-Finnish) · 2/1,179,996 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,620 alleles · very rare exomes 2/1,461,856 · genomes 0/151,764 · 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.Ala2Val
Coding: c.5C>T
MANE Select: NM_003001
dbSNP: rs781337432
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

hereditary pheochromocytoma-paraganglioma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma/paraganglioma syndrome 3 gastrointestinal stromal tumor hereditary neoplastic syndrome

For Hereditary pheochromocytoma-paraganglioma (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Worldwide)

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.Ala2= Benign/Likely benign ★★ same residue
SDHC p.Ala2Asp Uncertain significance ★ 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-ala2val (accessed [today's date]).

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