Is SDHA p.Ser52Phe (c.155C>T) pathogenic?

SDHA p.Ser52Phe (c.155C>T) is classified Conflicting classifications of pathogenicity in SDHA (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-02-03). AlphaMissense: likely pathogenic (0.8624); Ultra-rare (popmax 0.05%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with SDHA p.Ser52Phe (c.155C>T)?

SDHA p.Ser52Phe (c.155C>T) is associated with hereditary neoplastic syndrome, Leigh syndrome, dilated cardiomyopathy 1GG (ClinVar).

How common is SDHA p.Ser52Phe (c.155C>T) in the general population?

SDHA p.Ser52Phe (c.155C>T) is ultra-rare (popmax 0.05%, amr) (gnomAD).

What do computational predictors say about SDHA p.Ser52Phe (c.155C>T)?

AlphaMissense predicts likely pathogenic (score 0.8624) — an in-silico prediction, not a clinical call.

SDHA p.Ser52Phe

c.155C>T · rs377470390 · VCV252906

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely pathogenic

0.8624 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.05%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8624	likely pathogenic
REVEL	0.587	indeterminate
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 38 kb · p 1.1e-12 · regional, not allelic
Overall
CADD	25.3	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 0.05% Admixed American · 30/60,006 alleles

Filtering AF 0.0359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0312%

Overall 0.00732% 118/1,613,024 alleles · ultra-rare exomes 107/1,460,818 · genomes 11/152,206 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.05%	2,000
Middle Eastern	0.036%	2,781
Remaining individualsnot grpmax-eligible	0.016%	6,239
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,802
European (non-Finnish)	0.0061%	16,385
Finnishnot grpmax-eligible	0.00156%	64,042
African / African-American	0.00134%	74,896

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.Ser52Phe
Coding: c.155C>T
MANE Select: NM_004168
dbSNP: rs377470390
Type: single nucleotide variant
Location: chr5:224364 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 5 PDB
Residue 52: an α-helix

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

Disease context

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

Also linked: Leigh syndrome dilated cardiomyopathy 1GG pheochromocytoma/paraganglioma syndrome 5 hereditary pheochromocytoma-paraganglioma neurodegeneration with ataxia and late-onset optic atrophy mitochondrial disease mitochondrial complex II deficiency, nuclear type 1 diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype

Similar variants

SDHA p.Ser52Thr Uncertain significance ★★ ⚠ same residue
SDHA p.Ser52= Benign ★ same residue
SDHA c.1064+1G>A Likely pathogenic ★★ same condition
SDHA c.1064+1G>T Likely pathogenic ★★ same condition
SDHA c.1064+2T>A Likely pathogenic ★★ same condition
SDHA c.1065-2A>G Likely pathogenic ★★ same condition
SDHA c.1260+1G>T Likely pathogenic ★★ same condition
SDHA c.1260+2T>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/sdha-p-ser52phe (accessed [today's date]).

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