Is XK p.Ser415Ala (c.1243T>G) pathogenic?

XK p.Ser415Ala (c.1243T>G) is classified Uncertain significance in XK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-06). AlphaMissense: likely benign (0.0685); Very rare (popmax 0.00653%, amr); Associated with Inborn genetic diseases.

What condition is associated with XK p.Ser415Ala (c.1243T>G)?

XK p.Ser415Ala (c.1243T>G) is associated with Inborn genetic diseases (ClinVar).

How common is XK p.Ser415Ala (c.1243T>G) in the general population?

XK p.Ser415Ala (c.1243T>G) is very rare (popmax 0.00653%, amr) (gnomAD).

What do computational predictors say about XK p.Ser415Ala (c.1243T>G)?

AlphaMissense predicts likely benign (score 0.0685) — an in-silico prediction, not a clinical call.

XK p.Ser415Ala

c.1243T>G · rs782782627 · VCV2178446

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00653%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0685	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -6.90	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 0.23	GERP -1.9, phastCons 0.005
Regional constraint	o/e 0.69	unconstrained · MANE · 42 kb · p 8.3e-09 · regional, not allelic
Overall
CADD	3.244	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 0.00653% Admixed American · 3/45,965 alleles

Filtering AF 0.00173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00088%

Overall 0.000273% 3/1,097,131 alleles · very rare

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.Ser415Ala
Coding: c.1243T>G
MANE Select: NM_021083
dbSNP: rs782782627
Type: single nucleotide variant
Location: chrX:37728370 (GRCh38)
Structure: AlphaFold pLDDT 81.89 · 1 PDB
Residue 415: the 'disordered' region; a UniProt-annotated variant site (in mclds)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

XK p.Arg138Trp Uncertain significance ★★ ⚠ same condition
XK p.Asn244Ser Uncertain significance ★★ ⚠ same condition
XK p.Glu265Gly Uncertain significance ★★ ⚠ same condition
XK p.Leu185Ser Uncertain significance ★★ ⚠ same condition
XK p.Ser140= Benign/Likely benign ★★ same condition
XK p.Lys339Ter Pathogenic ★ same condition
XK p.Ala149Val Uncertain significance ★ same condition
XK p.Asp418Tyr Uncertain significance ★ ⚠ 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/xk-p-ser415ala (accessed [today's date]).

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