Is CSKMT p.Pro66Ala (c.196C>G) pathogenic?

CSKMT p.Pro66Ala (c.196C>G) is classified Uncertain significance in CSKMT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: likely benign (0.1339); Very rare (popmax 0.00136%, nfe).

How common is CSKMT p.Pro66Ala (c.196C>G) in the general population?

CSKMT p.Pro66Ala (c.196C>G) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about CSKMT p.Pro66Ala (c.196C>G)?

AlphaMissense predicts likely benign (score 0.1339) — an in-silico prediction, not a clinical call.

CSKMT p.Pro66Ala

c.196C>G · VCV3836727

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1339 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1339	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -9.77	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 3.5	GERP 0.72, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 1,168 bp · p 0.082 · regional, not allelic
Overall
CADD	19.72	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 0.00136% European (non-Finnish) · 16/1,180,052 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00105% 17/1,614,024 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00136%	73,753
South Asian	0.0011%	91,090

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: CSKMT
Protein: p.Pro66Ala
Coding: c.196C>G
MANE Select: NM_001043229
Type: single nucleotide variant
Location: chr11:62666524 (GRCh38)
Gene constraint: LOEUF 1.856 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.80

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

Similar variants

CSKMT p.Ala135Thr Uncertain significance ★ ⚠ same type
CSKMT p.Ala168Thr Uncertain significance ★ ⚠ same type
CSKMT p.Ala31Thr Uncertain significance ★ ⚠ same type
CSKMT p.Ala71Thr Uncertain significance ★ ⚠ same type
CSKMT p.Arg171Pro Uncertain significance ★ ⚠ same type
CSKMT p.Arg171Trp Uncertain significance ★ ⚠ same type
CSKMT p.Arg186Gly Uncertain significance ★ ⚠ same type
CSKMT p.Arg19Gly 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/cskmt-p-pro66ala (accessed [today's date]).

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