Is SDHD p.Ala82Ser (c.244G>T) pathogenic?

SDHD p.Ala82Ser (c.244G>T) is classified Uncertain significance in SDHD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-29). AlphaMissense: likely benign (0.1958); Very rare (popmax 0.00439%, sas); Associated with Cowden syndrome 3.

What condition is associated with SDHD p.Ala82Ser (c.244G>T)?

SDHD p.Ala82Ser (c.244G>T) is associated with Cowden syndrome 3, pheochromocytoma, Carney-Stratakis syndrome (ClinVar).

How common is SDHD p.Ala82Ser (c.244G>T) in the general population?

SDHD p.Ala82Ser (c.244G>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about SDHD p.Ala82Ser (c.244G>T)?

AlphaMissense predicts likely benign (score 0.1958) — an in-silico prediction, not a clinical call.

SDHD p.Ala82Ser

c.244G>T · rs745559875 · VCV1039073

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1958 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cowden syndrome 3

Computational evidence

Protein change
AlphaMissense	0.1958	likely benign
REVEL	0.821	moderately pathogenic-leaning
SaProt	LLR -9.34	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 2.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	24.6	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 0.00439% South Asian · 4/91,076 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000248% 4/1,613,720 alleles · very rare exomes 3/1,461,566 · genomes 1/152,154 · 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.Ala82Ser
Coding: c.244G>T
MANE Select: NM_003002
dbSNP: rs745559875
Type: single nucleotide variant
Location: chr11:112088941 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB
Residue 82: 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.Ala82Pro Uncertain significance ★★ ⚠ same residue
SDHD p.Ala82= Likely benign ★ 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
SDHD c.315-2A>T Pathogenic/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-ala82ser (accessed [today's date]).

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