Is SDHD p.Ala90Ser (c.268G>T) pathogenic?

SDHD p.Ala90Ser (c.268G>T) is classified Uncertain significance in SDHD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-24). AlphaMissense: likely benign (0.1403); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary pheochromocytoma-paraganglioma.

What condition is associated with SDHD p.Ala90Ser (c.268G>T)?

SDHD p.Ala90Ser (c.268G>T) is associated with hereditary pheochromocytoma-paraganglioma, hereditary neoplastic syndrome (ClinVar).

How common is SDHD p.Ala90Ser (c.268G>T) in the general population?

SDHD p.Ala90Ser (c.268G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Hereditary pheochromocytoma-paraganglioma inherited?

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

What do computational predictors say about SDHD p.Ala90Ser (c.268G>T)?

AlphaMissense predicts likely benign (score 0.1403) — an in-silico prediction, not a clinical call.

SDHD p.Ala90Ser

c.268G>T · rs765102002 · VCV1794788

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1403 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary pheochromocytoma-paraganglioma

Computational evidence

Protein change
AlphaMissense	0.1403	likely benign
REVEL	0.697	pathogenic-leaning
SaProt	LLR -9.76	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.4	GERP 2.1, phastCons 0.94
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	22.9	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,012 alleles

Overall 6.2e-05% 1/1,614,076 alleles · very rare exomes 1/1,461,840 · genomes 0/152,236 · 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.Ala90Ser
Coding: c.268G>T
MANE Select: NM_003002
dbSNP: rs765102002
Type: single nucleotide variant
Location: chr11:112088965 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB
Residue 90: an α-helix

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

Disease context

hereditary pheochromocytoma-paraganglioma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Hereditary pheochromocytoma-paraganglioma (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

SDHD p.Ala90Gly Uncertain significance ★★ ⚠ same residue
SDHD p.Ala90Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHD p.Ala90Val Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHD p.Ala90Leu Uncertain significance ★★ same residue
SDHD p.Ala90_Ser94del Likely pathogenic ★ same residue
SDHD p.Ala90fs Pathogenic ★ same residue
SDHD p.Ala90Thr Uncertain significance ★ ⚠ same residue
SDHD p.Ala90= Likely benign ★ same residue

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-ala90ser (accessed [today's date]).

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