Is SDHD p.Leu85Phe (c.255G>T) pathogenic?

SDHD p.Leu85Phe (c.255G>T) is classified Conflicting classifications of pathogenicity in SDHD (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-09). AlphaMissense: likely benign (0.0843); Very rare (popmax 0.00446%, eas); Associated with Paragangliomas with sensorineural hearing loss.

What condition is associated with SDHD p.Leu85Phe (c.255G>T)?

SDHD p.Leu85Phe (c.255G>T) is associated with Paragangliomas with sensorineural hearing loss, pheochromocytoma, Carney-Stratakis syndrome (ClinVar).

How common is SDHD p.Leu85Phe (c.255G>T) in the general population?

SDHD p.Leu85Phe (c.255G>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about SDHD p.Leu85Phe (c.255G>T)?

AlphaMissense predicts likely benign (score 0.0843) — an in-silico prediction, not a clinical call.

SDHD p.Leu85Phe

c.255G>T · rs199517389 · VCV135198

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0843 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Paragangliomas with sensorineural hearing loss

Computational evidence

Protein change
AlphaMissense	0.0843	likely benign
REVEL	0.607	indeterminate
SaProt	LLR -6.31	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 6.5	GERP 0.17, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	20.6	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 0.00446% East Asian · 2/44,880 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,614,028 alleles · very rare exomes 2/1,461,758 · genomes 0/152,270 · 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.Leu85Phe
Coding: c.255G>T
MANE Select: NM_003002
dbSNP: rs199517389
Type: single nucleotide variant
Location: chr11:112088952 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB
Residue 85: an α-helix

Full SDHD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Paragangliomas with sensorineural hearing loss — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

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
SDHD c.315-2A>T Pathogenic/Likely pathogenic ★★ same condition
SDHD p.Arg22Ter 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-leu85phe (accessed [today's date]).

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