Is SDHAF2 p.Ser8Pro (c.22T>C) pathogenic?

SDHAF2 p.Ser8Pro (c.22T>C) is classified Likely benign in SDHAF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-26). AlphaMissense: likely benign (0.0585); Very rare (popmax 0.000169%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with SDHAF2 p.Ser8Pro (c.22T>C)?

SDHAF2 p.Ser8Pro (c.22T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is SDHAF2 p.Ser8Pro (c.22T>C) in the general population?

SDHAF2 p.Ser8Pro (c.22T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about SDHAF2 p.Ser8Pro (c.22T>C)?

AlphaMissense predicts likely benign (score 0.0585) — an in-silico prediction, not a clinical call.

SDHAF2 p.Ser8Pro

c.22T>C · rs2540110958 · VCV1789274

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0585 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0585	likely benign
REVEL	0.165	moderately benign-leaning
SaProt	LLR -7.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.64	GERP -1.9
Regional constraint	o/e 0.97	unconstrained · MANE · 16 kb · p 0.71 · regional, not allelic
Overall
CADD	10.24	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 0.000169% European (non-Finnish) · 2/1,180,036 alleles

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

Overall 0.000124% 2/1,614,218 alleles · very rare exomes 2/1,461,856 · genomes 0/152,362 · 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.Ser8Pro
Coding: c.22T>C
MANE Select: NM_017841
dbSNP: rs2540110958
Type: single nucleotide variant
Location: chr11:61430168 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.06 · 2 PDB

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

Similar variants

SDHAF2 p.Ser8Leu Uncertain significance ★★ ⚠ same residue
SDHAF2 p.Ser8Trp Uncertain significance ★★ ⚠ same residue
SDHAF2 p.Ser8Ter Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHAF2 p.Ser8Thr Uncertain significance ★ ⚠ same residue
SDHAF2 p.Ser8= Likely benign ★★ 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

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-ser8pro (accessed [today's date]).

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