Is COPE p.Ser77Leu (c.230C>T) pathogenic?

COPE p.Ser77Leu (c.230C>T) is classified Uncertain significance in COPE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-07). AlphaMissense: likely benign (0.1214); Ultra-rare (popmax 0.0187%, afr).

How common is COPE p.Ser77Leu (c.230C>T) in the general population?

COPE p.Ser77Leu (c.230C>T) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about COPE p.Ser77Leu (c.230C>T)?

AlphaMissense predicts likely benign (score 0.1214) — an in-silico prediction, not a clinical call.

COPE p.Ser77Leu

c.230C>T · VCV3268955

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1214 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1214	likely benign
REVEL	0.255	benign-leaning
SaProt	LLR -9.78	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 8.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 20 kb · p 0.49 · regional, not allelic
Overall
CADD	25.4	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 0.0187% African / African-American · 14/75,038 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00903%

Overall 0.00254% 41/1,614,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,360
Remaining individualsnot grpmax-eligible	0.0048%	20,835
South Asian	0.00329%	30,361
European (non-Finnish)	0.00169%	59,001
Admixed American	0.00167%	60,022

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: COPE
Protein: p.Ser77Leu
Coding: c.230C>T
MANE Select: NM_007263
Type: single nucleotide variant
Location: chr19:18911031 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.20 · 2 PDB

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

Similar variants

COPE p.Ala124Thr Uncertain significance ★ ⚠ same type
COPE p.Ala139Val Uncertain significance ★ ⚠ same type
COPE p.Ala185Thr Uncertain significance ★ ⚠ same type
COPE p.Ala224Thr Uncertain significance ★ ⚠ same type
COPE p.Ala25Thr Uncertain significance ★ ⚠ same type
COPE p.Ala2Gly Uncertain significance ★ ⚠ same type
COPE p.Ala308Thr Uncertain significance ★ ⚠ same type
COPE p.Ala59Val 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/cope-p-ser77leu (accessed [today's date]).

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