Is CPLX1 p.Lys75Glu (c.223A>G) pathogenic?

CPLX1 p.Lys75Glu (c.223A>G) is classified Uncertain significance in CPLX1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-03). AlphaMissense: likely pathogenic (0.6766); Ultra-rare (popmax 0.0201%, amr); Associated with Inborn genetic diseases.

What condition is associated with CPLX1 p.Lys75Glu (c.223A>G)?

CPLX1 p.Lys75Glu (c.223A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CPLX1 p.Lys75Glu (c.223A>G) in the general population?

CPLX1 p.Lys75Glu (c.223A>G) is ultra-rare (popmax 0.0201%, amr) (gnomAD).

What do computational predictors say about CPLX1 p.Lys75Glu (c.223A>G)?

AlphaMissense predicts likely pathogenic (score 0.6766) — an in-silico prediction, not a clinical call.

CPLX1 p.Lys75Glu

c.223A>G · rs376234900 · VCV3250708

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6766 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6766	likely pathogenic
REVEL	0.297	indeterminate
SaProt	LLR -8.10	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 1.28	unconstrained · MANE · 38 kb · p 0.0001 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0201% Admixed American · 12/59,792 alleles

Filtering AF 0.0116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00901%

Overall 0.00709% 114/1,607,692 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0201%	4,983
African / African-American	0.0148%	6,776
European (non-Finnish)	0.00705%	14,181
South Asian	0.00551%	18,138
Remaining individualsnot grpmax-eligible	0.00483%	20,712

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: CPLX1
Protein: p.Lys75Glu
Coding: c.223A>G
MANE Select: NM_006651
dbSNP: rs376234900
Type: single nucleotide variant
Location: chr4:786683 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI 0.44 (gnomAD)
Structure: AlphaFold pLDDT 72.31 · 2 PDB
Residue 75: the 'disordered' region

Full CPLX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CPLX1 p.Lys75Arg Uncertain significance ★ ⚠ same residue
CPLX1 p.Asp113Glu Uncertain significance ★★ ⚠ same condition
CPLX1 p.Asp29Ala Uncertain significance ★★ ⚠ same condition
CPLX1 p.Gly104Asp Uncertain significance ★★ ⚠ same condition
CPLX1 p.Val109Ala Uncertain significance ★★ ⚠ same condition
CPLX1 p.Ala40Val Uncertain significance ★ ⚠ same condition
CPLX1 p.Ala80Thr Uncertain significance ★ ⚠ same condition
CPLX1 p.Ala88Pro Uncertain significance ★ ⚠ same condition

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/cplx1-p-lys75glu (accessed [today's date]).

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