Is CSK p.Met192Thr (c.575T>C) pathogenic?

CSK p.Met192Thr (c.575T>C) is classified Uncertain significance in CSK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-24). AlphaMissense: likely benign (0.1437); Very rare (popmax 0.00192%, amr).

How common is CSK p.Met192Thr (c.575T>C) in the general population?

CSK p.Met192Thr (c.575T>C) is very rare (popmax 0.00192%, amr) (gnomAD).

What do computational predictors say about CSK p.Met192Thr (c.575T>C)?

AlphaMissense predicts likely benign (score 0.1437) — an in-silico prediction, not a clinical call.

CSK p.Met192Thr

c.575T>C · VCV4656998

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1437 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00192%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1437	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -5.16	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 5.1	GERP 1.1, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 3,413 bp · p 1e-25 · regional, not allelic
Overall
CADD	19.89	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 0.00192% Admixed American · 1/52,144 alleles

Overall 0.000142% 2/1,406,764 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00192%	52,144
South Asian	0.00118%	85,008

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.Met192Thr
Coding: c.575T>C
MANE Select: NM_004383
Type: single nucleotide variant
Location: chr15:74800699 (GRCh38)
Gene constraint: LOEUF 0.222 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.57 · 6 PDB
Residue 192: an α-helix

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-met192thr (accessed [today's date]).

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