Is CBLC p.Arg390His (c.1169G>A) pathogenic?

CBLC p.Arg390His (c.1169G>A) is classified Uncertain significance in CBLC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-02). AlphaMissense: likely benign (0.3131); Ultra-rare (popmax 0.0165%, mid).

How common is CBLC p.Arg390His (c.1169G>A) in the general population?

CBLC p.Arg390His (c.1169G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CBLC p.Arg390His (c.1169G>A)?

AlphaMissense predicts likely benign (score 0.3131) — an in-silico prediction, not a clinical call.

CBLC p.Arg390His

c.1169G>A · VCV3485653

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3131 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3131	likely benign
REVEL	0.885	moderately pathogenic-leaning
SaProt	LLR -12.73	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 2.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.99 · regional, not allelic
Overall
CADD	32.0	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 0.0165% Middle Eastern · 1/6,058 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00416% 67/1,612,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
Finnishnot grpmax-eligible	0.0141%	7,108
Ashkenazi Jewishnot grpmax-eligible	0.00677%	14,769
East Asian	0.0067%	14,933
European (non-Finnish)	0.0039%	25,637
South Asian	0.00331%	30,230
Admixed American	0.00168%	59,570
Remaining individualsnot grpmax-eligible	0.0016%	62,402
African / African-American	0.00134%	74,816

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: CBLC
Protein: p.Arg390His
Coding: c.1169G>A
MANE Select: NM_012116
Type: single nucleotide variant
Location: chr19:44793505 (GRCh38)
Gene constraint: LOEUF 1.058 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.85 · 7 PDB
Residue 390: the 'interaction with ret' region

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

Similar variants

CBLC p.Ala122Ser Uncertain significance ★ ⚠ same type
CBLC p.Ala137Val Uncertain significance ★ ⚠ same type
CBLC p.Ala21Val Uncertain significance ★ ⚠ same type
CBLC p.Ala377Pro Uncertain significance ★ ⚠ same type
CBLC p.Ala398Val Uncertain significance ★ ⚠ same type
CBLC p.Ala433Ser Uncertain significance ★ ⚠ same type
CBLC p.Ala450Gly Uncertain significance ★ ⚠ same type
CBLC p.Ala465Val 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/cblc-p-arg390his (accessed [today's date]).

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