Is MALT1 p.Phe420Ile (c.1258T>A) pathogenic?

MALT1 p.Phe420Ile (c.1258T>A) is classified Uncertain significance in MALT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-08). AlphaMissense: likely pathogenic (0.9408); Absent from gnomAD v4.1; Associated with combined immunodeficiency due to MALT1 deficiency.

What condition is associated with MALT1 p.Phe420Ile (c.1258T>A)?

MALT1 p.Phe420Ile (c.1258T>A) is associated with combined immunodeficiency due to MALT1 deficiency (ClinVar).

How common is MALT1 p.Phe420Ile (c.1258T>A) in the general population?

MALT1 p.Phe420Ile (c.1258T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MALT1 p.Phe420Ile (c.1258T>A)?

AlphaMissense predicts likely pathogenic (score 0.9408) — an in-silico prediction, not a clinical call.

MALT1 p.Phe420Ile

Q: How is Combined immunodeficiency due to MALT1 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1258T>A · rs2511552958 · VCV2015027

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9408 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined immunodeficiency due to MALT1 deficiency

Computational evidence

Protein change
AlphaMissense	0.9408	likely pathogenic
REVEL	0.145	moderately benign-leaning
SaProt	LLR -8.58	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.6, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 19 kb · p 4.4e-18 · regional, not allelic
Overall
CADD	25.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MALT1
Protein: p.Phe420Ile
Coding: c.1258T>A
MANE Select: NM_006785
dbSNP: rs2511552958
Type: single nucleotide variant
Location: chr18:58733432 (GRCh38)
Gene constraint: LOEUF 0.58 · pLI 0.64 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.09 · 27 PDB
Residue 420: the 'caspase-like' region

Full MALT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined immunodeficiency due to MALT1 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to MALT1 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

MALT1 p.Arg191Ter Pathogenic ★★ same condition
MALT1 c.1753+5G>A Uncertain significance ★★ same condition
MALT1 p.Ala413Val Uncertain significance ★★ ⚠ same condition
MALT1 p.Ala774Pro Uncertain significance ★★ ⚠ same condition
MALT1 p.Ala791Thr Uncertain significance ★★ ⚠ same condition
MALT1 p.Arg149Gln Uncertain significance ★★ ⚠ same condition
MALT1 p.Arg296Gln Uncertain significance ★★ ⚠ same condition
MALT1 p.Arg354Pro Uncertain significance ★★ ⚠ same condition

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/malt1-p-phe420ile (accessed [today's date]).

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