Is SDHD p.Val110Ile (c.328G>A) pathogenic?

SDHD p.Val110Ile (c.328G>A) is classified Uncertain significance in SDHD (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-30). AlphaMissense: likely benign (0.1108); Very rare (popmax 0.00134%, afr); Associated with mitochondrial complex 2 deficiency, nuclear type 3.

What condition is associated with SDHD p.Val110Ile (c.328G>A)?

SDHD p.Val110Ile (c.328G>A) is associated with mitochondrial complex 2 deficiency, nuclear type 3, pheochromocytoma, Carney-Stratakis syndrome (ClinVar).

How common is SDHD p.Val110Ile (c.328G>A) in the general population?

SDHD p.Val110Ile (c.328G>A) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about SDHD p.Val110Ile (c.328G>A)?

AlphaMissense predicts likely benign (score 0.1108) — an in-silico prediction, not a clinical call.

SDHD p.Val110Ile

c.328G>A · rs1060503771 · VCV412500

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1108 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

mitochondrial complex 2 deficiency, nuclear type 3

Computational evidence

Protein change
AlphaMissense	0.1108	likely benign
REVEL	0.618	indeterminate
SaProt	LLR -5.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	19.52	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,864 alleles

Overall 6.2e-05% 1/1,611,900 alleles · very rare exomes 0/1,459,668 · genomes 1/152,232 · 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.Val110Ile
Coding: c.328G>A
MANE Select: NM_003002
dbSNP: rs1060503771
Type: single nucleotide variant
Location: chr11:112094818 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB
Residue 110: 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 Carney-Stratakis syndrome Cowden syndrome 3 hereditary neoplastic syndrome hereditary pheochromocytoma-paraganglioma

Similar variants

SDHD p.Val110Gly Uncertain significance ★ ⚠ same residue
SDHD p.Val110Leu Uncertain significance ★ ⚠ same residue
SDHD p.Val110= 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

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-val110ile (accessed [today's date]).

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