Is COBLL1 p.Asp331Ala (c.992A>C) pathogenic?

COBLL1 p.Asp331Ala (c.992A>C) is classified Uncertain significance in COBLL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-26). AlphaMissense: likely benign (0.1); Very rare (popmax 0.00446%, nfe).

How common is COBLL1 p.Asp331Ala (c.992A>C) in the general population?

COBLL1 p.Asp331Ala (c.992A>C) is very rare (popmax 0.00446%, nfe) (gnomAD).

What do computational predictors say about COBLL1 p.Asp331Ala (c.992A>C)?

AlphaMissense predicts likely benign (score 0.1) — an in-silico prediction, not a clinical call.

COBLL1 p.Asp331Ala

c.992A>C · VCV3268431

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -6.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ1.00 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.9	GERP 1.1, phastCons 0.32
Regional constraint	o/e 1.01	unconstrained · MANE · 155 kb · p 0.72 · regional, not allelic
Overall
CADD	19.39	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 0.00446% European (non-Finnish) · 52/1,166,932 alleles

Filtering AF 0.00346% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00313%

Overall 0.00334% 53/1,587,492 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00446%	22,441
Remaining individualsnot grpmax-eligible	0.00164%	61,106

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: COBLL1
Protein: p.Asp331Ala
Coding: c.992A>C
MANE Select: NM_001365672
Type: single nucleotide variant
Location: chr2:164722079 (GRCh38)
Gene constraint: LOEUF 0.664 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.51 · 1 PDB
Residue 331: the 'disordered' region

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-asp331ala (accessed [today's date]).

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