Is SDHD p.Pro28Ser (c.82C>T) pathogenic?

SDHD p.Pro28Ser (c.82C>T) is classified Uncertain significance in SDHD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-25). AlphaMissense: likely benign (0.1461); Very rare (popmax 0.00329%, sas); Associated with Carney-Stratakis syndrome.

What condition is associated with SDHD p.Pro28Ser (c.82C>T)?

SDHD p.Pro28Ser (c.82C>T) is associated with Carney-Stratakis syndrome, pheochromocytoma, Cowden syndrome 3 (ClinVar).

How common is SDHD p.Pro28Ser (c.82C>T) in the general population?

SDHD p.Pro28Ser (c.82C>T) is very rare (popmax 0.00329%, sas) (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.Pro28Ser (c.82C>T)?

AlphaMissense predicts likely benign (score 0.1461) — an in-silico prediction, not a clinical call.

SDHD p.Pro28Ser

c.82C>T · rs541477171 · VCV939509

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1461 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Carney-Stratakis syndrome

Computational evidence

Protein change
AlphaMissense	0.1461	likely benign
REVEL	0.578	indeterminate
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 2.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	21.7	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 0.00329% South Asian · 3/91,078 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000248% 4/1,613,726 alleles · very rare exomes 3/1,461,394 · genomes 1/152,332 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,359
European (non-Finnish)	8.48e-05%	1,179,640

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.Pro28Ser
Coding: c.82C>T
MANE Select: NM_003002
dbSNP: rs541477171
Type: single nucleotide variant
Location: chr11:112087886 (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.Pro28Arg Uncertain significance ★★ ⚠ same residue
SDHD p.Pro28His Uncertain significance ★★ ⚠ same residue
SDHD p.Pro28Thr Uncertain significance ★★ ⚠ same residue
SDHD p.Pro28Ala Uncertain significance ★ ⚠ same residue
SDHD p.Pro28Leu Uncertain significance ★ ⚠ same residue
SDHD p.Pro28= Likely benign ★ same residue
SDHD c.170-1G>T Pathogenic ★★ same condition
SDHD c.170-2A>G 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-pro28ser (accessed [today's date]).

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