Is CALML4 p.Ile131Phe (c.391A>T) pathogenic?

CALML4 p.Ile131Phe (c.391A>T) is classified Uncertain significance in CALML4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-17). AlphaMissense: ambiguous (0.5312); Very rare (popmax 0.0011%, sas).

How common is CALML4 p.Ile131Phe (c.391A>T) in the general population?

CALML4 p.Ile131Phe (c.391A>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CALML4 p.Ile131Phe (c.391A>T)?

AlphaMissense predicts ambiguous (score 0.5312) — an in-silico prediction, not a clinical call.

CALML4 p.Ile131Phe

c.391A>T · VCV3826964

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5312 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Computational evidence

Protein change
AlphaMissense	0.5312	ambiguous
REVEL	0.342	indeterminate
SaProt	LLR -11.26	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.15	GERP -0.74, phastCons 0.022
Regional constraint	o/e 1.04	unconstrained · MANE · 11 kb · p 0.56 · regional, not allelic
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I174F vs ClinVar I131F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,082 alleles

Overall 6.84e-05% 1/1,461,564 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: CALML4
Protein: p.Ile131Phe
Coding: c.391A>T
MANE Select: NM_033429
Type: single nucleotide variant
Location: chr15:68194086 (GRCh38)
Gene constraint: LOEUF 1.374 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.70
Residue 131: the ef-hand 3 domain

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

Similar variants

CALML4 p.Ile131Leu Uncertain significance ★ ⚠ same residue
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

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-ile131phe (accessed [today's date]).

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