Is CALML4 p.Gln50Arg (c.149A>G) pathogenic?

CALML4 p.Gln50Arg (c.149A>G) is classified Uncertain significance in CALML4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-04). AlphaMissense: likely benign (0.151); Ultra-rare (popmax 0.0165%, mid).

How common is CALML4 p.Gln50Arg (c.149A>G) in the general population?

CALML4 p.Gln50Arg (c.149A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CALML4 p.Gln50Arg (c.149A>G)?

AlphaMissense predicts likely benign (score 0.151) — an in-silico prediction, not a clinical call.

CALML4 p.Gln50Arg

c.149A>G · rs199655041 · VCV2280148

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.151 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.151	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -6.44	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 0.036	GERP -1.6, phastCons 0.022
Regional constraint	o/e 1.04	unconstrained · MANE · 11 kb · p 0.56 · regional, not allelic
Overall
CADD	14.65	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM Q93R vs ClinVar Q50R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,076 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000992% 16/1,613,580 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,076
Admixed American	0.00167%	59,954
European (non-Finnish)	0.00119%	84,281

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: CALML4
Protein: p.Gln50Arg
Coding: c.149A>G
MANE Select: NM_033429
dbSNP: rs199655041
Type: single nucleotide variant
Location: chr15:68199567 (GRCh38)
Gene constraint: LOEUF 1.374 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.70

Full CALML4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CALML4 c.-23C>G Uncertain significance ★ ⚠ same type
CALML4 c.-69G>A Uncertain significance ★ ⚠ same type
CALML4 p.Arg107Trp Uncertain significance ★ ⚠ same type
CALML4 p.Arg151Trp Uncertain significance ★ ⚠ same type
CALML4 p.Asn134Asp Uncertain significance ★ ⚠ same type
CALML4 p.Asp8Tyr Uncertain significance ★ ⚠ same type
CALML4 p.Asp94Asn Uncertain significance ★ ⚠ same type
CALML4 p.Gln79Glu 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/calml4-p-gln50arg (accessed [today's date]).

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