Is COP1 p.Met299Val (c.895A>G) pathogenic?

COP1 p.Met299Val (c.895A>G) is classified Benign in COP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-07-06). AlphaMissense: likely benign (0.1573); Rare (popmax 0.101%, nfe).

How common is COP1 p.Met299Val (c.895A>G) in the general population?

COP1 p.Met299Val (c.895A>G) is rare (popmax 0.101%, nfe) (gnomAD).

What do computational predictors say about COP1 p.Met299Val (c.895A>G)?

AlphaMissense predicts likely benign (score 0.1573) — an in-silico prediction, not a clinical call.

COP1 p.Met299Val

c.895A>G · rs41266110 · VCV721265

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1573 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.101%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1573	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -5.74	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.29	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 83 kb · p 0.064 · regional, not allelic
Overall
CADD	22.7	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 0.101% European (non-Finnish) · 1,182/1,165,110 alleles

Filtering AF 0.0966% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0947%

Overall 0.106% 1,688/1,595,356 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.12%	89
Remaining individualsnot grpmax-eligible	0.165%	605
European (non-Finnish)grpmax	0.101%	986
Admixed American	0.0826%	1,211
Finnishnot grpmax-eligible	0.0282%	3,547
Middle Eastern	0.0167%	5,984
African / African-American	0.00939%	10,646

Ashkenazi Jewish 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: COP1
Protein: p.Met299Val
Coding: c.895A>G
MANE Select: NM_022457
dbSNP: rs41266110
Type: single nucleotide variant
Location: chr1:176135083 (GRCh38)
Gene constraint: LOEUF 0.557 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 75.64 · 7 PDB

Full COP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COP1 c.1142-7C>T Likely benign ★★ same type
COP1 p.Arg295Thr Benign ★★ ⚠ same type
COP1 p.Ala117Val Uncertain significance ★ ⚠ same type
COP1 p.Ala12Ser Uncertain significance ★ ⚠ same type
COP1 p.Ala354Val Uncertain significance ★ ⚠ same type
COP1 p.Ala457Val Uncertain significance ★ ⚠ same type
COP1 p.Ala7Val Uncertain significance ★ ⚠ same type
COP1 p.Arg378Cys 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/cop1-p-met299val (accessed [today's date]).

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