Is XK p.Ser115Pro (c.343T>C) pathogenic?

XK p.Ser115Pro (c.343T>C) is classified Uncertain significance in XK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-04). AlphaMissense: likely benign (0.2199); Very rare (popmax 0.00515%, nfe).

How common is XK p.Ser115Pro (c.343T>C) in the general population?

XK p.Ser115Pro (c.343T>C) is very rare (popmax 0.00515%, nfe) (gnomAD).

What do computational predictors say about XK p.Ser115Pro (c.343T>C)?

AlphaMissense predicts likely benign (score 0.2199) — an in-silico prediction, not a clinical call.

XK p.Ser115Pro

c.343T>C · rs1275693406 · VCV1303649

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2199 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00515%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2199	likely benign
REVEL	0.284	benign-leaning
SaProt	LLR -5.12	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 5	GERP 2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 42 kb · p 8.3e-09 · regional, not allelic
Overall
CADD	21.0	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 0.00515% European (non-Finnish) · 46/892,813 alleles

Filtering AF 0.00395% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00353%

Overall 0.0039% 47/1,206,247 alleles · very rare exomes 45/1,094,215 · genomes 2/112,032 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00515%	19,409
Remaining individualsnot grpmax-eligible	0.00211%	47,425

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: XK
Protein: p.Ser115Pro
Coding: c.343T>C
MANE Select: NM_021083
dbSNP: rs1275693406
Type: single nucleotide variant
Location: chrX:37694383 (GRCh38)
Structure: AlphaFold pLDDT 81.89 · 1 PDB
Residue 115: a modified residue (phosphoserine)

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

Similar variants

XK p.Arg133Ter Pathogenic ★★ same type
XK p.Arg222Ter Pathogenic/Likely pathogenic ★★ same type
XK p.Arg138Trp Uncertain significance ★★ ⚠ same type
XK p.Asn244Ser Uncertain significance ★★ ⚠ same type
XK p.Glu265Gly Uncertain significance ★★ ⚠ same type
XK p.Leu185Ser Uncertain significance ★★ ⚠ same type
XK p.Ser415Ala Uncertain significance ★★ ⚠ same type
XK p.Trp36Cys 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/xk-p-ser115pro (accessed [today's date]).

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