Is COBLL1 p.Pro1122Ser (c.3364C>T) pathogenic?

COBLL1 p.Pro1122Ser (c.3364C>T) is classified Likely benign in COBLL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.063); Very rare (popmax 0.00017%, nfe).

How common is COBLL1 p.Pro1122Ser (c.3364C>T) in the general population?

COBLL1 p.Pro1122Ser (c.3364C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about COBLL1 p.Pro1122Ser (c.3364C>T)?

AlphaMissense predicts likely benign (score 0.063) — an in-silico prediction, not a clinical call.

COBLL1 p.Pro1122Ser

c.3364C>T · VCV4231552

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.063 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.063	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -5.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.14	GERP -4.9, phastCons 0.55
Regional constraint	o/e 1.01	unconstrained · MANE · 155 kb · p 0.72 · regional, not allelic
Overall
CADD	0.031	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 0.00017% European (non-Finnish) · 2/1,176,282 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,456,820 alleles · very rare

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.Pro1122Ser
Coding: c.3364C>T
MANE Select: NM_001365672
Type: single nucleotide variant
Location: chr2:164685969 (GRCh38)
Gene constraint: LOEUF 0.664 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.51 · 1 PDB
Residue 1122: 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-pro1122ser (accessed [today's date]).

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