Is SDHD p.His56Pro (c.167A>C) pathogenic?

SDHD p.His56Pro (c.167A>C) is classified Uncertain significance in SDHD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-07). AlphaMissense: likely benign (0.0772); Very rare (popmax 0.00446%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with SDHD p.His56Pro (c.167A>C)?

SDHD p.His56Pro (c.167A>C) is associated with hereditary neoplastic syndrome, pheochromocytoma, Carney-Stratakis syndrome (ClinVar).

How common is SDHD p.His56Pro (c.167A>C) in the general population?

SDHD p.His56Pro (c.167A>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about SDHD p.His56Pro (c.167A>C)?

AlphaMissense predicts likely benign (score 0.0772) — an in-silico prediction, not a clinical call.

SDHD p.His56Pro

c.167A>C · rs1555186817 · VCV465223

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0772 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0772	likely benign
REVEL	0.586	indeterminate
SaProt	LLR -5.74	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 2.3	GERP 1, phastCons 0.001
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	16.85	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 0.00446% East Asian · 2/44,796 alleles

Filtering AF 0.00074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000125% 2/1,595,314 alleles · very rare exomes 1/1,443,188 · genomes 1/152,126 · 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.His56Pro
Coding: c.167A>C
MANE Select: NM_003002
dbSNP: rs1555186817
Type: single nucleotide variant
Location: chr11:112087971 (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.His56Arg Uncertain significance ★★ ⚠ same residue
SDHD p.His56Gln Uncertain significance ★★ ⚠ same residue
SDHD p.His56= 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

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-his56pro (accessed [today's date]).

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