Is SDHD p.Ala33Glu (c.98C>A) pathogenic?

SDHD p.Ala33Glu (c.98C>A) is classified Uncertain significance in SDHD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-19). AlphaMissense: likely benign (0.1827); Absent from gnomAD v4.1; Associated with Paragangliomas with sensorineural hearing loss.

What condition is associated with SDHD p.Ala33Glu (c.98C>A)?

SDHD p.Ala33Glu (c.98C>A) is associated with Paragangliomas with sensorineural hearing loss, pheochromocytoma, Carney-Stratakis syndrome (ClinVar).

How common is SDHD p.Ala33Glu (c.98C>A) in the general population?

SDHD p.Ala33Glu (c.98C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SDHD p.Ala33Glu (c.98C>A)?

AlphaMissense predicts likely benign (score 0.1827) — an in-silico prediction, not a clinical call.

SDHD p.Ala33Glu

c.98C>A · rs1566692246 · VCV1996565

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1827 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Paragangliomas with sensorineural hearing loss

Computational evidence

Protein change
AlphaMissense	0.1827	likely benign
REVEL	0.574	indeterminate
SaProt	LLR -8.97	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 2.6	GERP 2.1, phastCons 0.99
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	19.36	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

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.Ala33Glu
Coding: c.98C>A
MANE Select: NM_003002
dbSNP: rs1566692246
Type: single nucleotide variant
Location: chr11:112087902 (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

Paragangliomas with sensorineural hearing loss — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma Carney-Stratakis syndrome Cowden syndrome 3

Similar variants

SDHD p.Ala33= Likely benign ★★ same residue
SDHD p.Ala33Thr Uncertain significance ★ ⚠ same residue
SDHD p.Ala33fs Pathogenic ★★ same residue
SDHD p.Ala33Val 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

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-ala33glu (accessed [today's date]).

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