Is SDHD p.Ala29Pro (c.85G>C) pathogenic?

SDHD p.Ala29Pro (c.85G>C) is classified Uncertain significance in SDHD (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-02). AlphaMissense: likely benign (0.1133); Very rare (popmax 0.00223%, eas); Associated with mitochondrial complex 2 deficiency, nuclear type 3.

What condition is associated with SDHD p.Ala29Pro (c.85G>C)?

SDHD p.Ala29Pro (c.85G>C) is associated with mitochondrial complex 2 deficiency, nuclear type 3, pheochromocytoma/paraganglioma syndrome 1, pheochromocytoma (ClinVar).

How common is SDHD p.Ala29Pro (c.85G>C) in the general population?

SDHD p.Ala29Pro (c.85G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about SDHD p.Ala29Pro (c.85G>C)?

AlphaMissense predicts likely benign (score 0.1133) — an in-silico prediction, not a clinical call.

SDHD p.Ala29Pro

c.85G>C · rs776930864 · VCV412496

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1133 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex 2 deficiency, nuclear type 3

Computational evidence

Protein change
AlphaMissense	0.1133	likely benign
REVEL	0.659	pathogenic-leaning
SaProt	LLR -6.58	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 8.2	GERP 2.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	22.6	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 0.00223% East Asian · 1/44,880 alleles

Overall 0.000186% 3/1,613,830 alleles · very rare exomes 3/1,461,556 · genomes 0/152,274 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,880
Admixed American	0.00167%	60,022
European (non-Finnish)	8.48e-05%	1,179,774

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.Ala29Pro
Coding: c.85G>C
MANE Select: NM_003002
dbSNP: rs776930864
Type: single nucleotide variant
Location: chr11:112087889 (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

mitochondrial complex 2 deficiency, nuclear type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma/paraganglioma syndrome 1 pheochromocytoma Carney-Stratakis syndrome Cowden syndrome 3 hereditary neoplastic syndrome hereditary pheochromocytoma-paraganglioma

Similar variants

SDHD p.Ala29Thr Uncertain significance ★★ ⚠ same residue
SDHD p.Ala29Val Uncertain significance ★ ⚠ same residue
SDHD p.Ala29= 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

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-ala29pro (accessed [today's date]).

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