Is COPS4 p.Cys70Ser (c.208T>A) pathogenic?

COPS4 p.Cys70Ser (c.208T>A) is classified Uncertain significance in COPS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-17). AlphaMissense: ambiguous (0.3703); Ultra-rare (popmax 0.0941%, sas).

How common is COPS4 p.Cys70Ser (c.208T>A) in the general population?

COPS4 p.Cys70Ser (c.208T>A) is ultra-rare (popmax 0.0941%, sas) (gnomAD).

What do computational predictors say about COPS4 p.Cys70Ser (c.208T>A)?

AlphaMissense predicts ambiguous (score 0.3703) — an in-silico prediction, not a clinical call.

COPS4 p.Cys70Ser

c.208T>A · VCV3835591

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3703 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0941%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3703	ambiguous
REVEL	0.171	moderately benign-leaning
SaProt	LLR -6.74	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 17 kb · p 2.2e-21 · regional, not allelic
Overall
CADD	21.4	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 0.0941% South Asian · 85/90,340 alleles

Filtering AF 0.0779% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0719%

Overall 0.0128% 207/1,611,806 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0941%	1,063
Admixed American	0.0469%	2,132
Remaining individualsnot grpmax-eligible	0.024%	4,161
Middle Eastern	0.0165%	6,054
European (non-Finnish)	0.00644%	15,516
African / African-American	0.00267%	37,427

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.Cys70Ser
Coding: c.208T>A
MANE Select: NM_016129
Type: single nucleotide variant
Location: chr4:83049219 (GRCh38)
Gene constraint: LOEUF 0.304 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.79 · 29 PDB
Residue 70: an α-helix

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

Similar variants

COPS4 p.Ala10Ser Uncertain significance ★ ⚠ same type
COPS4 p.Ala4Val Uncertain significance ★ ⚠ same type
COPS4 p.Arg27Cys Uncertain significance ★ ⚠ same type
COPS4 p.Arg27His Uncertain significance ★ ⚠ same type
COPS4 p.Arg27Pro 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

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-cys70ser (accessed [today's date]).

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