Is SDHA p.Val4Phe (c.10G>T) pathogenic?

SDHA p.Val4Phe (c.10G>T) is classified Uncertain significance in SDHA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-05). AlphaMissense: likely benign (0.0639); Very rare (popmax 0.00551%, eas); Associated with dilated cardiomyopathy 1GG.

What condition is associated with SDHA p.Val4Phe (c.10G>T)?

SDHA p.Val4Phe (c.10G>T) is associated with dilated cardiomyopathy 1GG, pheochromocytoma/paraganglioma syndrome 5, hereditary neoplastic syndrome (ClinVar).

How common is SDHA p.Val4Phe (c.10G>T) in the general population?

SDHA p.Val4Phe (c.10G>T) is very rare (popmax 0.00551%, eas) (gnomAD).

How is Familial isolated dilated cardiomyopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SDHA p.Val4Phe (c.10G>T)?

AlphaMissense predicts likely benign (score 0.0639) — an in-silico prediction, not a clinical call.

SDHA p.Val4Phe

c.10G>T · rs778069799 · VCV822169

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0639 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00551%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dilated cardiomyopathy 1GG

Computational evidence

Protein change
AlphaMissense	0.0639	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -7.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.39	GERP -2.6
Regional constraint	o/e 0.76	unconstrained · MANE · 38 kb · p 1.1e-12 · regional, not allelic
Overall
CADD	14.19	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 0.00551% East Asian · 2/36,274 alleles

Filtering AF 0.000913% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000342%

Overall 0.000343% 5/1,459,536 alleles · very rare exomes 4/1,307,346 · genomes 1/152,190 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00551%	18,137
Remaining individualsnot grpmax-eligible	0.0018%	55,578
African / African-American	0.00146%	68,322
European (non-Finnish)	8.97e-05%	1,114,748

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: SDHA
Protein: p.Val4Phe
Coding: c.10G>T
MANE Select: NM_004168
dbSNP: rs778069799
Type: single nucleotide variant
Location: chr5:218365 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 5 PDB

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

Disease context

dilated cardiomyopathy 1GG — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma/paraganglioma syndrome 5 hereditary neoplastic syndrome mitochondrial complex II deficiency, nuclear type 1

For Familial isolated dilated cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

SDHA p.Val4Gly Uncertain significance ★★ ⚠ same residue
SDHA p.Val4Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHA p.Val4Asp Uncertain significance ★ ⚠ same residue
SDHA p.Val4Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHA p.Val4= Likely benign ★ same residue
SDHA p.Val4fs Pathogenic ★★ same residue
SDHA c.1064+1G>A Likely pathogenic ★★ same condition
SDHA c.1064+1G>T 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/sdha-p-val4phe (accessed [today's date]).

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