Is SDHD p.Ala9Ser (c.25G>T) pathogenic?

SDHD p.Ala9Ser (c.25G>T) is classified Uncertain significance in SDHD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-31). AlphaMissense: likely benign (0.084); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with SDHD p.Ala9Ser (c.25G>T)?

SDHD p.Ala9Ser (c.25G>T) is associated with hereditary neoplastic syndrome, pheochromocytoma, Carney-Stratakis syndrome (ClinVar).

How common is SDHD p.Ala9Ser (c.25G>T) in the general population?

SDHD p.Ala9Ser (c.25G>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about SDHD p.Ala9Ser (c.25G>T)?

AlphaMissense predicts likely benign (score 0.084) — an in-silico prediction, not a clinical call.

SDHD p.Ala9Ser

c.25G>T · rs772671893 · VCV643986

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.084 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.084	likely benign
REVEL	0.493	indeterminate
SaProt	LLR -5.65	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 3.5	GERP 2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	15.49	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 0.00223% East Asian · 1/44,902 alleles

Overall 0.000186% 3/1,614,124 alleles · very rare exomes 2/1,461,892 · genomes 1/152,232 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,902
South Asian	0.0011%	91,096
European (non-Finnish)	8.47e-05%	1,180,038

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.Ala9Ser
Coding: c.25G>T
MANE Select: NM_003002
dbSNP: rs772671893
Type: single nucleotide variant
Location: chr11:112086932 (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

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

Also linked: pheochromocytoma Carney-Stratakis syndrome Cowden syndrome 3

Similar variants

SDHD p.Ala9= 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>C Pathogenic/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-ala9ser (accessed [today's date]).

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