Is CKAP2 p.Pro127Leu (c.380C>T) pathogenic?

CKAP2 p.Pro127Leu (c.380C>T) is classified Likely benign in CKAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-24). AlphaMissense: likely benign (0.0621); Ultra-rare (popmax 0.0165%, mid).

How common is CKAP2 p.Pro127Leu (c.380C>T) in the general population?

CKAP2 p.Pro127Leu (c.380C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CKAP2 p.Pro127Leu (c.380C>T)?

AlphaMissense predicts likely benign (score 0.0621) — an in-silico prediction, not a clinical call.

CKAP2 p.Pro127Leu

c.380C>T · VCV3267459

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0621 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0621	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -5.89	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 0.81	GERP -0.94
Regional constraint	o/e 1.06	unconstrained · MANE · 6,978 bp · p 0.17 · regional, not allelic
Overall
CADD	1.452	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P128L vs ClinVar P127L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000821% 12/1,461,662 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.008%	12,499
South Asian	0.0022%	45,489
African / African-American	0.00133%	75,016
European (non-Finnish)	0.000254%	393,321

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: CKAP2
Protein: p.Pro127Leu
Coding: c.380C>T
MANE Select: NM_018204
Type: single nucleotide variant
Location: chr13:52461206 (GRCh38)
Gene constraint: LOEUF 0.983 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.29

Full CKAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CKAP2 p.Arg628Gln Uncertain significance ★★ ⚠ same type
CKAP2 p.Asn386Asp Benign ★★ same type
CKAP2 p.Thr312= Benign ★★ same type
CKAP2 p.Ala214Ser Uncertain significance ★ ⚠ same type
CKAP2 p.Ala326Thr Uncertain significance ★ ⚠ same type
CKAP2 p.Ala347Ser Uncertain significance ★ ⚠ same type
CKAP2 p.Ala350Thr Uncertain significance ★ ⚠ same type
CKAP2 p.Ala614Ser 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/ckap2-p-pro127leu (accessed [today's date]).

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