Is COPS4 p.Arg27His (c.80G>A) pathogenic?

COPS4 p.Arg27His (c.80G>A) is classified Uncertain significance in COPS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-18). AlphaMissense: likely pathogenic (0.5917); Very rare (popmax 0.00223%, eas).

How common is COPS4 p.Arg27His (c.80G>A) in the general population?

COPS4 p.Arg27His (c.80G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about COPS4 p.Arg27His (c.80G>A)?

AlphaMissense predicts likely pathogenic (score 0.5917) — an in-silico prediction, not a clinical call.

COPS4 p.Arg27His

c.80G>A · rs201720335 · VCV3076277

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5917 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5917	likely pathogenic
REVEL	0.233	benign-leaning
SaProt	LLR -7.01	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 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.32 · regional, not allelic
Overall
CADD	27.6	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 0.00223% East Asian · 1/44,748 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000745% 12/1,611,510 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,748
South Asian	0.0011%	91,010
European (non-Finnish)	0.000849%	117,801

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: COPS4
Protein: p.Arg27His
Coding: c.80G>A
MANE Select: NM_016129
dbSNP: rs201720335
Type: single nucleotide variant
Location: chr4:83045631 (GRCh38)
Gene constraint: LOEUF 0.304 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.79 · 29 PDB
Residue 27: an α-helix

Full COPS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPS4 p.Arg27Cys Uncertain significance ★ ⚠ same residue
COPS4 p.Arg27Pro Uncertain significance ★ ⚠ same residue
COPS4 p.Ala10Ser Uncertain significance ★ ⚠ same type
COPS4 p.Ala4Val Uncertain significance ★ ⚠ same type
COPS4 p.Arg364Gln Uncertain significance ★ ⚠ same type
COPS4 p.Asn180Ser Uncertain significance ★ ⚠ same type
COPS4 p.Asp8Gly Uncertain significance ★ ⚠ same type
COPS4 p.Cys70Ser 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/cops4-p-arg27his (accessed [today's date]).

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