Is GSKIP p.Ser11Arg (c.33C>A) pathogenic?

GSKIP p.Ser11Arg (c.33C>A) is classified Uncertain significance in GSKIP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: likely benign (0.2505); Ultra-rare (popmax 0.039%, afr).

How common is GSKIP p.Ser11Arg (c.33C>A) in the general population?

GSKIP p.Ser11Arg (c.33C>A) is ultra-rare (popmax 0.039%, afr) (gnomAD).

What do computational predictors say about GSKIP p.Ser11Arg (c.33C>A)?

AlphaMissense predicts likely benign (score 0.2505) — an in-silico prediction, not a clinical call.

GSKIP p.Ser11Arg

c.33C>A · rs562745853 · VCV2471049

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2505 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.039%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2505	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -7.83	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 0.41	GERP 1.7, phastCons 0.97
Regional constraint	o/e 0.90	unconstrained · MANE · 3,433 bp · p 0.2 · regional, not allelic
Overall
CADD	16.19	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 0.039% African / African-American · 29/74,434 alleles

Filtering AF 0.0278% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0241%

Overall 0.00193% 31/1,610,030 alleles · ultra-rare exomes 15/1,459,076 · genomes 16/150,954 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.039%	2,567
Remaining individualsnot grpmax-eligible	0.00321%	31,185

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: GSKIP
Protein: p.Ser11Arg
Coding: c.33C>A
MANE Select: NM_016472
dbSNP: rs562745853
Type: single nucleotide variant
Location: chr14:96382280 (GRCh38)
Gene constraint: LOEUF 0.86 · pLI 0.52 (gnomAD)
Structure: AlphaFold pLDDT 84.59 · 1 PDB
Residue 11: the 'disordered' region; a β-strand

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

Similar variants

GSKIP c.258+57A>G Benign ★★ same type
GSKIP c.-1-107T>C Benign ★★ same type
GSKIP c.*50T>C Benign ★★ same type
GSKIP p.Ala125Thr Uncertain significance ★ ⚠ same type
GSKIP p.Arg119Gln Uncertain significance ★ ⚠ same type
GSKIP p.Arg129Thr Uncertain significance ★ ⚠ same type
GSKIP p.Arg58Trp Uncertain significance ★ ⚠ same type
GSKIP p.Asn74Lys 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/gskip-p-ser11arg (accessed [today's date]).

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