Is SDHD p.Pro53Leu (c.158C>T) pathogenic?

SDHD p.Pro53Leu (c.158C>T) is classified Uncertain significance in SDHD (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0978); Ultra-rare (popmax 0.0494%, mid); Associated with Paragangliomas with sensorineural hearing loss.

What condition is associated with SDHD p.Pro53Leu (c.158C>T)?

SDHD p.Pro53Leu (c.158C>T) is associated with Paragangliomas with sensorineural hearing loss, pheochromocytoma, Carney-Stratakis syndrome (ClinVar).

How common is SDHD p.Pro53Leu (c.158C>T) in the general population?

SDHD p.Pro53Leu (c.158C>T) is ultra-rare (popmax 0.0494%, mid) (gnomAD).

What do computational predictors say about SDHD p.Pro53Leu (c.158C>T)?

AlphaMissense predicts likely benign (score 0.0978) — an in-silico prediction, not a clinical call.

SDHD p.Pro53Leu

c.158C>T · rs149516118 · VCV161388

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0978 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Paragangliomas with sensorineural hearing loss

Computational evidence

Protein change
AlphaMissense	0.0978	likely benign
REVEL	0.778	moderately pathogenic-leaning
SaProt	LLR -7.63	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.24	donor loss · deltas
Pangolin	Δ0.22	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	24.6	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 0.0494% Middle Eastern · 3/6,072 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00717%

Overall 0.00243% 39/1,604,708 alleles · ultra-rare exomes 34/1,452,530 · genomes 5/152,178 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0494%	2,024
Remaining individualsnot grpmax-eligible	0.00965%	10,366
Admixed American	0.00667%	14,999
South Asian	0.0033%	30,307
African / African-American	0.00268%	37,361
East Asian	0.00223%	44,850
European (non-Finnish)	0.00171%	58,576

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.Pro53Leu
Coding: c.158C>T
MANE Select: NM_003002
dbSNP: rs149516118
Type: single nucleotide variant
Location: chr11:112087962 (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

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 p.Pro53Ala Uncertain significance ★★ ⚠ same residue
SDHD p.Pro53= Benign/Likely benign ★★ same residue
SDHD p.Pro53del 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

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-pro53leu (accessed [today's date]).

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