Is SDHD p.Ala130Val (c.389C>T) pathogenic?

SDHD p.Ala130Val (c.389C>T) is classified Uncertain significance in SDHD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-18). AlphaMissense: likely benign (0.077); Very rare (popmax 8.48e-05%, nfe); Associated with Cowden syndrome 3.

What condition is associated with SDHD p.Ala130Val (c.389C>T)?

SDHD p.Ala130Val (c.389C>T) is associated with Cowden syndrome 3, pheochromocytoma, Carney-Stratakis syndrome (ClinVar).

How common is SDHD p.Ala130Val (c.389C>T) in the general population?

SDHD p.Ala130Val (c.389C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SDHD p.Ala130Val (c.389C>T)?

AlphaMissense predicts likely benign (score 0.077) — an in-silico prediction, not a clinical call.

SDHD p.Ala130Val

c.389C>T · rs1049692537 · VCV2933102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.077 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cowden syndrome 3

Computational evidence

Protein change
AlphaMissense	0.077	likely benign
REVEL	0.249	benign-leaning
SaProt	LLR -7.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.20	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -0.03	GERP -2.5, phastCons 0.001
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	9.625	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,706 alleles

Overall 6.2e-05% 1/1,611,868 alleles · very rare exomes 1/1,459,538 · genomes 0/152,330 · 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: SDHD
Protein: p.Ala130Val
Coding: c.389C>T
MANE Select: NM_003002
dbSNP: rs1049692537
Type: single nucleotide variant
Location: chr11:112094879 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB
Residue 130: an α-helix

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

Disease context

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

Also linked: pheochromocytoma Carney-Stratakis syndrome

Similar variants

SDHD p.Ala130Gly Uncertain significance ★★ ⚠ same residue
SDHD p.Ala130Pro Uncertain significance ★★ ⚠ same residue
SDHD p.Ala130= Likely benign ★★ same residue
SDHD p.Ala130Ser Uncertain significance ★ ⚠ same residue
SDHD p.Ala130fs Pathogenic/Likely pathogenic ★★ same residue
SDHD c.170-1G>T Pathogenic ★★ same condition
SDHD c.170-2A>G Pathogenic/Likely pathogenic ★★ same condition
SDHD c.314+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/sdhd-p-ala130val (accessed [today's date]).

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