Is SDHD p.Ala61Pro (c.181G>C) pathogenic?

SDHD p.Ala61Pro (c.181G>C) is classified Uncertain significance in SDHD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-05). AlphaMissense: likely benign (0.2553); Absent from gnomAD v4.1; Associated with Carney-Stratakis syndrome.

What condition is associated with SDHD p.Ala61Pro (c.181G>C)?

SDHD p.Ala61Pro (c.181G>C) is associated with Carney-Stratakis syndrome, pheochromocytoma, Cowden syndrome 3 (ClinVar).

How common is SDHD p.Ala61Pro (c.181G>C) in the general population?

SDHD p.Ala61Pro (c.181G>C) is absent from gnomAD v4.1 (gnomAD).

How is Carney-Stratakis syndrome inherited?

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

What do computational predictors say about SDHD p.Ala61Pro (c.181G>C)?

AlphaMissense predicts likely benign (score 0.2553) — an in-silico prediction, not a clinical call.

SDHD p.Ala61Pro

c.181G>C · rs2498904440 · VCV2948182

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2553 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Carney-Stratakis syndrome

Computational evidence

Protein change
AlphaMissense	0.2553	likely benign
REVEL	0.732	pathogenic-leaning
SaProt	LLR -13.14	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	23.9	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: SDHD
Protein: p.Ala61Pro
Coding: c.181G>C
MANE Select: NM_003002
dbSNP: rs2498904440
Type: single nucleotide variant
Location: chr11:112088878 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB

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

Disease context

Carney-Stratakis syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma Cowden syndrome 3 hereditary neoplastic syndrome

For Carney-Stratakis syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

SDHD p.Ala61= Benign/Likely benign ★★ same residue
SDHD p.Ala61Ser Uncertain significance ★ ⚠ same residue
SDHD p.Ala61Val Uncertain significance ★ ⚠ 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
SDHD c.314+1G>T Pathogenic ★★ same condition
SDHD c.315-1G>A 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/sdhd-p-ala61pro (accessed [today's date]).

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