Is CDS1 p.Pro63Leu (c.188C>T) pathogenic?

CDS1 p.Pro63Leu (c.188C>T) is classified Uncertain significance in CDS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-11). AlphaMissense: likely benign (0.0729); Ultra-rare (popmax 0.0529%, nfe).

How common is CDS1 p.Pro63Leu (c.188C>T) in the general population?

CDS1 p.Pro63Leu (c.188C>T) is ultra-rare (popmax 0.0529%, nfe) (gnomAD).

What do computational predictors say about CDS1 p.Pro63Leu (c.188C>T)?

AlphaMissense predicts likely benign (score 0.0729) — an in-silico prediction, not a clinical call.

CDS1 p.Pro63Leu

c.188C>T · rs202224063 · VCV2351910

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0729 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0529%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0729	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -7.08	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 2.6	GERP 0.094, phastCons 0.98
Overall
CADD	17.0	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 0.0529% European (non-Finnish) · 623/1,178,184 alleles

Filtering AF 0.0494% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0481%

Overall 0.0401% 646/1,611,920 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0529%	1,891
Remaining individualsnot grpmax-eligible	0.024%	4,161
African / African-American	0.004%	24,985
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,582
Admixed American	0.00333%	29,999
Finnishnot grpmax-eligible	0.00312%	32,009

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: CDS1
Protein: p.Pro63Leu
Coding: c.188C>T
MANE Select: NM_007194 · reported on NM_001263
dbSNP: rs202224063
Type: single nucleotide variant
Location: chr4:84604313 (GRCh38)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 63: the 'disordered' region

Full CDS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHEK2 p.Leu63= Benign/Likely benign ★★ same residue
CHEK2 p.Leu63Ter Pathogenic ★ same residue
CHEK2 p.Leu63Ser Uncertain significance ★ ⚠ same residue
CHEK2 p.Leu63Val Uncertain significance ★ ⚠ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same type
CHEK2 c.1008+1G>T Likely pathogenic ★★ same type
CHEK2 c.1008+2T>A Likely pathogenic ★★ same type
CHEK2 c.1008+2T>G Likely pathogenic ★★ 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/cds1-p-pro63leu (accessed [today's date]).

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