Is COBL p.Pro1053Arg (c.3158C>G) pathogenic?

COBL p.Pro1053Arg (c.3158C>G) is classified Uncertain significance in COBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely benign (0.0665); Very rare (popmax 0.0067%, nfe).

How common is COBL p.Pro1053Arg (c.3158C>G) in the general population?

COBL p.Pro1053Arg (c.3158C>G) is very rare (popmax 0.0067%, nfe) (gnomAD).

What do computational predictors say about COBL p.Pro1053Arg (c.3158C>G)?

AlphaMissense predicts likely benign (score 0.0665) — an in-silico prediction, not a clinical call.

COBL p.Pro1053Arg

c.3158C>G · VCV4655312

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0665 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0067%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0665	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.88	GERP -0.84, phastCons 0.001
Regional constraint	o/e 1.02	unconstrained · MANE · 119 kb · p 0.54 · regional, not allelic
Overall
CADD	1.31	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 0.0067% European (non-Finnish) · 79/1,179,500 alleles

Filtering AF 0.00547% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00506%

Overall 0.00508% 82/1,613,238 alleles · very rare exomes 75/1,460,900 · genomes 7/152,338 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0067%	14,930
Remaining individualsnot grpmax-eligible	0.0032%	31,232
African / African-American	0.00133%	74,994

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: COBL
Protein: p.Pro1053Arg
Coding: c.3158C>G
MANE Select: NM_015198
Type: single nucleotide variant
Location: chr7:51027938 (GRCh38)
Gene constraint: LOEUF 0.638 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.88 · 1 PDB
Residue 1053: the 'disordered' region

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

Similar variants

COBL p.Ala57= Benign ★★ same type
COBL p.Ala655Pro Benign ★★ same type
COBL p.Gly534Ser Likely benign ★★ same type
COBL p.His601Tyr Benign ★★ same type
COBL p.Ser47= Benign ★★ same type
COBL p.Ser513Phe Benign ★★ same type
COBL p.Thr1234= Benign ★★ same type
COBL p.Tyr222= Benign ★★ 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/cobl-p-pro1053arg (accessed [today's date]).

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