Is COBLL1 p.Val993Ala (c.2978T>C) pathogenic?

COBLL1 p.Val993Ala (c.2978T>C) is classified Uncertain significance in COBLL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-30). AlphaMissense: likely pathogenic (0.8562); Absent from gnomAD v4.1.

How common is COBLL1 p.Val993Ala (c.2978T>C) in the general population?

COBLL1 p.Val993Ala (c.2978T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COBLL1 p.Val993Ala (c.2978T>C)?

AlphaMissense predicts likely pathogenic (score 0.8562) — an in-silico prediction, not a clinical call.

COBLL1 p.Val993Ala

c.2978T>C · VCV4655338

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8562 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8562	likely pathogenic · top 7% in COBLL1
REVEL	0.208	benign-leaning
SaProt	LLR -4.40	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 2.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 155 kb · p 0.72 · regional, not allelic
Overall
CADD	24.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COBLL1
Protein: p.Val993Ala
Coding: c.2978T>C
MANE Select: NM_001365672
Type: single nucleotide variant
Location: chr2:164694414 (GRCh38)
Gene constraint: LOEUF 0.664 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.51 · 1 PDB

Full COBLL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COBLL1 p.Arg381His Likely benign ★★ same type
COBLL1 c.1225+1238G>A Uncertain significance ★ same type
COBLL1 c.1225+1259T>C Uncertain significance ★ same type
COBLL1 c.1225+1313C>T Uncertain significance ★ same type
COBLL1 p.Ala1011Val Uncertain significance ★ ⚠ same type
COBLL1 p.Ala1017Val Uncertain significance ★ ⚠ same type
COBLL1 p.Ala1124Asp Uncertain significance ★ ⚠ same type
COBLL1 p.Ala289Val 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/cobll1-p-val993ala (accessed [today's date]).

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