Is SDHD p.Leu76= (c.228C>T) pathogenic?

SDHD p.Leu76= (c.228C>T) is classified Conflicting classifications of pathogenicity in SDHD (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-19). Ultra-rare (popmax 0.0365%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with SDHD p.Leu76= (c.228C>T)?

SDHD p.Leu76= (c.228C>T) is associated with hereditary neoplastic syndrome, pheochromocytoma/paraganglioma syndrome 1, pheochromocytoma (ClinVar).

How common is SDHD p.Leu76= (c.228C>T) in the general population?

SDHD p.Leu76= (c.228C>T) is ultra-rare (popmax 0.0365%, mid) (gnomAD).

SDHD p.Leu76=

c.228C>T · rs148634289 · VCV465228

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0365%, mid)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.27	GERP 0.41, phastCons 0.97
Overall
CADD	10.25	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0365% Middle Eastern · 2/5,484 alleles

Filtering AF 0.00638% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00263%

Overall 0.000558% 9/1,613,272 alleles · ultra-rare exomes 6/1,461,088 · genomes 3/152,184 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0365%	2,742
African / African-American	0.00267%	37,445
South Asian	0.0011%	91,032
European (non-Finnish)	0.000339%	294,998

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.Leu76=
Coding: c.228C>T
MANE Select: NM_003002
dbSNP: rs148634289
Type: single nucleotide variant
Location: chr11:112088925 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB
Residue 76: an α-helix

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/paraganglioma syndrome 1 pheochromocytoma Carney-Stratakis syndrome Cowden syndrome 3 hereditary pheochromocytoma-paraganglioma

Similar variants

SDHD p.Leu76Phe Uncertain significance ★★ ⚠ same residue
SDHD p.Leu76Pro 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-leu76 (accessed [today's date]).

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