Is CSK p.Val41Ile (c.121G>A) pathogenic?

CSK p.Val41Ile (c.121G>A) is classified Uncertain significance in CSK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-16). AlphaMissense: likely benign (0.0882); Very rare (popmax 0.00203%, nfe).

How common is CSK p.Val41Ile (c.121G>A) in the general population?

CSK p.Val41Ile (c.121G>A) is very rare (popmax 0.00203%, nfe) (gnomAD).

What do computational predictors say about CSK p.Val41Ile (c.121G>A)?

AlphaMissense predicts likely benign (score 0.0882) — an in-silico prediction, not a clinical call.

CSK p.Val41Ile

c.121G>A · VCV3497592

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0882 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0882	likely benign
REVEL	0.139	moderately benign-leaning
SaProt	LLR -6.43	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 3,413 bp · p 1e-25 · regional, not allelic
Overall
CADD	23.4	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 0.00203% European (non-Finnish) · 24/1,179,872 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00155% 25/1,613,428 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00203%	49,161
Admixed American	0.00167%	59,990

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: CSK
Protein: p.Val41Ile
Coding: c.121G>A
MANE Select: NM_004383
Type: single nucleotide variant
Location: chr15:74798720 (GRCh38)
Gene constraint: LOEUF 0.222 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.57 · 6 PDB
Residue 41: the sh3 domain; a β-strand; the 'interaction with ptpn22' region

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

Similar variants

CSK p.Gly287Asp Benign ★★ same type
CSK p.Ala407Thr Uncertain significance ★ ⚠ same type
CSK p.Arg56Cys Uncertain significance ★ ⚠ same type
CSK p.Arg56His Uncertain significance ★ ⚠ same type
CSK p.Arg94Gln Uncertain significance ★ ⚠ same type
CSK p.Asn46Lys Uncertain significance ★ ⚠ same type
CSK p.Asn63Ser Uncertain significance ★ ⚠ same type
CSK p.Asp123Asn 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/csk-p-val41ile (accessed [today's date]).

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