Is SDHAF2 p.Pro53Ser (c.157C>T) pathogenic?

SDHAF2 p.Pro53Ser (c.157C>T) is classified Uncertain significance in SDHAF2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-17). AlphaMissense: likely pathogenic (0.7239); Very rare (popmax 0.000169%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with SDHAF2 p.Pro53Ser (c.157C>T)?

SDHAF2 p.Pro53Ser (c.157C>T) is associated with hereditary neoplastic syndrome, hereditary pheochromocytoma-paraganglioma (ClinVar).

How common is SDHAF2 p.Pro53Ser (c.157C>T) in the general population?

SDHAF2 p.Pro53Ser (c.157C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about SDHAF2 p.Pro53Ser (c.157C>T)?

AlphaMissense predicts likely pathogenic (score 0.7239) — an in-silico prediction, not a clinical call.

SDHAF2 p.Pro53Ser

c.157C>T · rs1060503390 · VCV411603

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7239 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7239	likely pathogenic
REVEL	0.438	indeterminate
SaProt	LLR -11.63	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.33	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 16 kb · p 0.71 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000169% European (non-Finnish) · 2/1,179,982 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,138 alleles · very rare exomes 2/1,461,832 · genomes 0/152,306 · 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: SDHAF2
Protein: p.Pro53Ser
Coding: c.157C>T
MANE Select: NM_017841
dbSNP: rs1060503390
Type: single nucleotide variant
Location: chr11:61437745 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.06 · 2 PDB
Residue 53: an α-helix

Full SDHAF2 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: hereditary pheochromocytoma-paraganglioma

Similar variants

SDHAF2 p.Pro53Leu Uncertain significance ★★ same residue
SDHAF2 p.Pro53Thr Uncertain significance ★★ ⚠ same residue
SDHAF2 p.Pro53Arg Uncertain significance ★ ⚠ same residue
SDHAF2 c.260+1G>A Likely pathogenic ★★ same condition
SDHAF2 c.261-2A>G Likely pathogenic ★★ same condition
SDHAF2 c.261-2A>T Likely pathogenic ★★ same condition
SDHAF2 c.37-1G>C Pathogenic/Likely pathogenic ★★ same condition
SDHAF2 c.37-2A>G 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/sdhaf2-p-pro53ser (accessed [today's date]).

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