Is CPLX1 p.Lys75Arg (c.224A>G) pathogenic?

CPLX1 p.Lys75Arg (c.224A>G) is classified Uncertain significance in CPLX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-17). AlphaMissense: likely benign (0.0753); Very rare (popmax 0.000595%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CPLX1 p.Lys75Arg (c.224A>G)?

CPLX1 p.Lys75Arg (c.224A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CPLX1 p.Lys75Arg (c.224A>G) in the general population?

CPLX1 p.Lys75Arg (c.224A>G) is very rare (popmax 0.000595%, nfe) (gnomAD).

What do computational predictors say about CPLX1 p.Lys75Arg (c.224A>G)?

AlphaMissense predicts likely benign (score 0.0753) — an in-silico prediction, not a clinical call.

CPLX1 p.Lys75Arg

c.224A>G · VCV4616484

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0753 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000595%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0753	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -5.92	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 3.2	GERP 1.4, phastCons 1
Regional constraint	o/e 1.28	unconstrained · MANE · 38 kb · p 0.0001 · regional, not allelic
Overall
CADD	21.4	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 0.000595% European (non-Finnish) · 7/1,177,168 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000549% 8/1,456,280 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,200
European (non-Finnish)grpmax	0.000595%	168,167

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Lys75Arg
Coding: c.224A>G
MANE Select: NM_006651
Type: single nucleotide variant
Location: chr4:786682 (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.Lys75Glu 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-lys75arg (accessed [today's date]).

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