Is CLPS p.Glu81Asp (c.243G>T) pathogenic?

CLPS p.Glu81Asp (c.243G>T) is classified Uncertain significance in CLPS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.9462); Very rare (popmax 0.00167%, amr).

How common is CLPS p.Glu81Asp (c.243G>T) in the general population?

CLPS p.Glu81Asp (c.243G>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CLPS p.Glu81Asp (c.243G>T)?

AlphaMissense predicts likely pathogenic (score 0.9462) — an in-silico prediction, not a clinical call.

CLPS p.Glu81Asp

c.243G>T · VCV4654515

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9462 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9462	likely pathogenic
REVEL	0.261	benign-leaning
SaProt	LLR -5.61	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.25	GERP -2.1, phastCons 0.97
Regional constraint	o/e 0.99	unconstrained · MANE · 2,139 bp · p 0.89 · regional, not allelic
Overall
CADD	22.6	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 0.00167% Admixed American · 1/60,022 alleles

Overall 0.000205% 3/1,461,830 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,255
Admixed Americangrpmax	0.00167%	60,022

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: CLPS
Protein: p.Glu81Asp
Coding: c.243G>T
MANE Select: NM_001832
Type: single nucleotide variant
Location: chr6:35795242 (GRCh38)
Gene constraint: LOEUF 1.423 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.89
Residue 81: a disulfide bond

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

Similar variants

CLPS p.Ala50Val Uncertain significance ★ ⚠ same type
CLPS p.Asn43Ile Uncertain significance ★ ⚠ same type
CLPS p.Cys80Arg Uncertain significance ★ ⚠ same type
CLPS p.Glu65Lys Uncertain significance ★ ⚠ same type
CLPS p.Gly102Asp Uncertain significance ★ ⚠ same type
CLPS p.His47Gln Uncertain significance ★ ⚠ same type
CLPS p.Leu71Pro Uncertain significance ★ ⚠ same type
CLPS p.Lys77Glu 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/clps-p-glu81asp (accessed [today's date]).

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