Is SDHC p.Ala2= (c.6T>G) pathogenic?

SDHC p.Ala2= (c.6T>G) is classified Benign/Likely benign in SDHC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-27). Very rare (popmax 0.00269%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with SDHC p.Ala2= (c.6T>G)?

SDHC p.Ala2= (c.6T>G) is associated with hereditary neoplastic syndrome, pheochromocytoma/paraganglioma syndrome 3, gastrointestinal stromal tumor (ClinVar).

How common is SDHC p.Ala2= (c.6T>G) in the general population?

SDHC p.Ala2= (c.6T>G) is very rare (popmax 0.00269%, afr) (gnomAD).

SDHC p.Ala2=

c.6T>G · rs775353334 · VCV1570436

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00269%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.18	GERP -0.92, phastCons 0.69
Overall
CADD	10.94	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00269% African / African-American · 2/74,448 alleles

Filtering AF 0.000446% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000167%

Overall 0.000124% 2/1,613,326 alleles · very rare exomes 1/1,461,864 · genomes 1/151,462 · 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.Ala2=
Coding: c.6T>G
MANE Select: NM_003001
dbSNP: rs775353334
Type: single nucleotide variant
Location: chr1:161314411 (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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma/paraganglioma syndrome 3 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.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-ala2 (accessed [today's date]).

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