Is STK35 p.Pro148Ser (c.442C>T) pathogenic?

STK35 p.Pro148Ser (c.442C>T) is classified Uncertain significance in STK35 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-21). AlphaMissense: likely benign (0.0815); Very rare (popmax 0.0042%, afr).

How common is STK35 p.Pro148Ser (c.442C>T) in the general population?

STK35 p.Pro148Ser (c.442C>T) is very rare (popmax 0.0042%, afr) (gnomAD).

What do computational predictors say about STK35 p.Pro148Ser (c.442C>T)?

AlphaMissense predicts likely benign (score 0.0815) — an in-silico prediction, not a clinical call.

STK35 p.Pro148Ser

c.442C>T · rs1349405730 · VCV2256302

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0815 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0042%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0815	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -6.96	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 2.5	GERP 1.1, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 1,206 bp · p 0.00011 · regional, not allelic
Overall
CADD	19.47	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 0.0042% African / African-American · 3/71,368 alleles

Filtering AF 0.00112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000609%

Overall 0.000321% 5/1,556,012 alleles · very rare exomes 1/1,403,832 · genomes 4/152,180 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0042%	23,789
Admixed American	0.00183%	54,670
European (non-Finnish)	8.62e-05%	1,159,816

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: STK35
Protein: p.Pro148Ser
Coding: c.442C>T
MANE Select: NM_080836
dbSNP: rs1349405730
Type: single nucleotide variant
Location: chr20:2102915 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.52
Residue 148: the 'disordered' region

Full STK35 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

STK35 p.Pro148Leu Uncertain significance ★ ⚠ same residue
STK35 p.Ala120Val Uncertain significance ★ ⚠ same type
STK35 p.Ala132Thr Uncertain significance ★ ⚠ same type
STK35 p.Ala177Val Uncertain significance ★ ⚠ same type
STK35 p.Ala178Val Uncertain significance ★ ⚠ same type
STK35 p.Ala17Pro Uncertain significance ★ ⚠ same type
STK35 p.Ala180Val Uncertain significance ★ ⚠ same type
STK35 p.Ala184Thr Uncertain significance ★ ⚠ same type

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/stk35-p-pro148ser (accessed [today's date]).

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