Is COBL p.Ser191Arg (c.573C>A) pathogenic?

COBL p.Ser191Arg (c.573C>A) is classified Uncertain significance in COBL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-09). AlphaMissense: ambiguous (0.4644); Very rare (popmax 0.00636%, nfe).

How common is COBL p.Ser191Arg (c.573C>A) in the general population?

COBL p.Ser191Arg (c.573C>A) is very rare (popmax 0.00636%, nfe) (gnomAD).

What do computational predictors say about COBL p.Ser191Arg (c.573C>A)?

AlphaMissense predicts ambiguous (score 0.4644) — an in-silico prediction, not a clinical call.

COBL p.Ser191Arg

c.573C>A · VCV3268415

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4644 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00636%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4644	ambiguous
REVEL	0.147	moderately benign-leaning
SaProt	LLR -8.32	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.4	GERP 0.97, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 55 kb · p 3.5e-05 · regional, not allelic
Overall
CADD	18.5	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 0.00636% European (non-Finnish) · 75/1,180,040 alleles

Filtering AF 0.00519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00474%

Overall 0.00496% 80/1,614,048 alleles · very rare exomes 74/1,461,856 · genomes 6/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00636%	15,734
Finnishnot grpmax-eligible	0.00469%	21,344
Remaining individualsnot grpmax-eligible	0.0032%	31,242

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.Ser191Arg
Coding: c.573C>A
MANE Select: NM_015198
Type: single nucleotide variant
Location: chr7:51190962 (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-ser191arg (accessed [today's date]).

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