Is SDHD p.Ala18Val (c.53C>T) pathogenic?

SDHD p.Ala18Val (c.53C>T) is classified Conflicting classifications of pathogenicity in SDHD (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2025-11-25). AlphaMissense: likely benign (0.1141); Ultra-rare (popmax 0.0188%, nfe); Associated with Cowden syndrome 3.

What condition is associated with SDHD p.Ala18Val (c.53C>T)?

SDHD p.Ala18Val (c.53C>T) is associated with Cowden syndrome 3, pheochromocytoma/paraganglioma syndrome 1, pheochromocytoma (ClinVar).

How common is SDHD p.Ala18Val (c.53C>T) in the general population?

SDHD p.Ala18Val (c.53C>T) is ultra-rare (popmax 0.0188%, nfe) (gnomAD).

What do computational predictors say about SDHD p.Ala18Val (c.53C>T)?

AlphaMissense predicts likely benign (score 0.1141) — an in-silico prediction, not a clinical call.

SDHD p.Ala18Val

c.53C>T · rs192332761 · VCV302481

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.1141 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0188%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cowden syndrome 3

Computational evidence

Protein change
AlphaMissense	0.1141	likely benign
REVEL	0.484	indeterminate
SaProt	LLR -7.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.7	GERP 0.18, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	16.99	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 0.0188% European (non-Finnish) · 220/1,169,482 alleles

Filtering AF 0.0167% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.0145% 232/1,602,308 alleles · ultra-rare exomes 216/1,449,948 · genomes 16/152,360 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0188%	5,316
African / African-American	0.00802%	12,470
Remaining individualsnot grpmax-eligible	0.00645%	15,508
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,552
Finnishnot grpmax-eligible	0.00156%	63,984

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.Ala18Val
Coding: c.53C>T
MANE Select: NM_003002
dbSNP: rs192332761
Type: single nucleotide variant
Location: chr11:112087857 (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

Cowden syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma/paraganglioma syndrome 1 pheochromocytoma Carney-Stratakis syndrome hereditary neoplastic syndrome hereditary pheochromocytoma-paraganglioma mitochondrial complex 2 deficiency, nuclear type 3

Similar variants

SDHD p.Ala18= 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
SDHD c.315-2A>C Pathogenic/Likely pathogenic ★★ same condition
SDHD c.315-2A>T 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-ala18val (accessed [today's date]).

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