Is COBL p.Val68Ala (c.203T>C) pathogenic?

COBL p.Val68Ala (c.203T>C) is classified Uncertain significance in COBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-21). AlphaMissense: likely pathogenic (0.7142); Very rare (popmax 8.47e-05%, nfe).

How common is COBL p.Val68Ala (c.203T>C) in the general population?

COBL p.Val68Ala (c.203T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about COBL p.Val68Ala (c.203T>C)?

AlphaMissense predicts likely pathogenic (score 0.7142) — an in-silico prediction, not a clinical call.

COBL p.Val68Ala

c.203T>C · VCV4655315

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7142 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7142	likely pathogenic · top 10% in COBL
REVEL	0.195	benign-leaning
SaProt	LLR -11.36	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 126 kb · p 0.12 · regional, not allelic
Overall
CADD	25.6	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 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 6.2e-05% 1/1,614,096 alleles · very rare exomes 1/1,461,838 · genomes 0/152,258 · joint denominator

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.Val68Ala
Coding: c.203T>C
MANE Select: NM_015198
Type: single nucleotide variant
Location: chr7:51219783 (GRCh38)
Gene constraint: LOEUF 0.638 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.88 · 1 PDB

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-val68ala (accessed [today's date]).

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