Is SDHD p.His104= (c.312C>T) pathogenic?

SDHD p.His104= (c.312C>T) is classified Benign/Likely benign in SDHD (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-02-02). Low-frequency (popmax 2.19%, afr); Associated with mitochondrial complex 2 deficiency, nuclear type 3.

What condition is associated with SDHD p.His104= (c.312C>T)?

SDHD p.His104= (c.312C>T) is associated with mitochondrial complex 2 deficiency, nuclear type 3, pheochromocytoma/paraganglioma syndrome 1, pheochromocytoma (ClinVar).

How common is SDHD p.His104= (c.312C>T) in the general population?

SDHD p.His104= (c.312C>T) is low-frequency (popmax 2.19%, afr) (gnomAD).

SDHD p.His104=

c.312C>T · rs61734352 · VCV212145

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.19%, afr)

Conditions

mitochondrial complex 2 deficiency, nuclear type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.60 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.2	GERP 0.28, phastCons 1
Overall
CADD	14.37	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.19% African / African-American · 1,645/75,036 alleles

Filtering AF 2.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.07%

Overall 0.118% 1,911/1,614,152 alleles · low-frequency exomes 942/1,461,850 · genomes 969/152,302 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.19%	46
Admixed American	0.202%	496
Remaining individualsnot grpmax-eligible	0.168%	595
Middle Eastern	0.149%	673
South Asian	0.00329%	30,360
European (non-Finnish)	0.00237%	42,143

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.His104=
Coding: c.312C>T
MANE Select: NM_003002
dbSNP: rs61734352
Type: single nucleotide variant
Location: chr11:112089009 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB
Residue 104: an α-helix

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 pheochromocytoma/paraganglioma syndrome 3 Carney-Stratakis syndrome Cowden syndrome 3 hereditary neoplastic syndrome hereditary pheochromocytoma-paraganglioma

Similar variants

SDHD p.His104Asp Uncertain significance ★★ ⚠ same residue
SDHD p.His104Pro 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
SDHD c.315-1G>A Likely pathogenic ★★ same condition
SDHD c.315-2A>C 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-his104 (accessed [today's date]).

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