Is SDHD p.His65Pro (c.194A>C) pathogenic?

SDHD p.His65Pro (c.194A>C) is classified Uncertain significance in SDHD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-15). AlphaMissense: ambiguous (0.5351); Absent from gnomAD v4.1; Associated with hereditary pheochromocytoma-paraganglioma.

What condition is associated with SDHD p.His65Pro (c.194A>C)?

SDHD p.His65Pro (c.194A>C) is associated with hereditary pheochromocytoma-paraganglioma (ClinVar).

How common is SDHD p.His65Pro (c.194A>C) in the general population?

SDHD p.His65Pro (c.194A>C) is absent from gnomAD v4.1 (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.His65Pro (c.194A>C)?

AlphaMissense predicts ambiguous (score 0.5351) — an in-silico prediction, not a clinical call.

SDHD p.His65Pro

c.194A>C · rs780226013 · VCV3072724

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5351 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary pheochromocytoma-paraganglioma

Computational evidence

Protein change
AlphaMissense	0.5351	ambiguous
REVEL	0.99	strongly pathogenic-leaning
SaProt	LLR -15.66	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	27.9	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

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.His65Pro
Coding: c.194A>C
MANE Select: NM_003002
dbSNP: rs780226013
Type: single nucleotide variant
Location: chr11:112088891 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB
Residue 65: 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

For Hereditary pheochromocytoma-paraganglioma (Orphanet):

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

Similar variants

SDHD p.His65Arg Uncertain significance ★★ ⚠ same residue
SDHD p.His65Tyr Uncertain significance ★ ⚠ same residue
SDHD p.His65= Likely benign ★ same residue
SDHD c.170-1G>T Pathogenic ★★ same condition
SDHD c.314+1G>A Pathogenic ★★ same condition
SDHD p.Arg22Ter Pathogenic ★★ same condition
SDHD p.Arg38Ter Pathogenic ★★ same condition
SDHD p.Asp92Tyr 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-his65pro (accessed [today's date]).

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