Is CALML4 p.Pro44Leu (c.131C>T) pathogenic?

CALML4 p.Pro44Leu (c.131C>T) is classified Uncertain significance in CALML4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely pathogenic (0.8428); Ultra-rare (popmax 0.0154%, sas).

How common is CALML4 p.Pro44Leu (c.131C>T) in the general population?

CALML4 p.Pro44Leu (c.131C>T) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about CALML4 p.Pro44Leu (c.131C>T)?

AlphaMissense predicts likely pathogenic (score 0.8428) — an in-silico prediction, not a clinical call.

CALML4 p.Pro44Leu

c.131C>T · VCV4218360

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8428 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8428	likely pathogenic
REVEL	0.575	indeterminate
SaProt	LLR -16.31	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 11 kb · p 0.56 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 P87L vs ClinVar P44L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0154% South Asian · 14/91,052 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00235% 38/1,613,590 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,504
African / African-American	0.00801%	12,484
Remaining individualsnot grpmax-eligible	0.008%	12,500
Admixed American	0.00333%	29,992
East Asian	0.00223%	44,798
European (non-Finnish)	0.000848%	117,990

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.Pro44Leu
Coding: c.131C>T
MANE Select: NM_033429
Type: single nucleotide variant
Location: chr15:68199585 (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.Gln50Arg 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-pro44leu (accessed [today's date]).

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