Is LAMA4 p.Trp14Arg (c.40T>C) pathogenic?

LAMA4 p.Trp14Arg (c.40T>C) is classified Uncertain significance in LAMA4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-21). AlphaMissense: ambiguous (0.428); Very rare (popmax 0.00297%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with LAMA4 p.Trp14Arg (c.40T>C)?

LAMA4 p.Trp14Arg (c.40T>C) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1JJ (ClinVar).

How common is LAMA4 p.Trp14Arg (c.40T>C) in the general population?

LAMA4 p.Trp14Arg (c.40T>C) is very rare (popmax 0.00297%, nfe) (gnomAD).

What do computational predictors say about LAMA4 p.Trp14Arg (c.40T>C)?

AlphaMissense predicts ambiguous (score 0.428) — an in-silico prediction, not a clinical call.

LAMA4 p.Trp14Arg

c.40T>C · rs782293373 · VCV518375

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.428 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00297%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.428	ambiguous
REVEL	0.188	benign-leaning
SaProt	LLR -9.91	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP -0.14, phastCons 0.97
Regional constraint	o/e 0.95	unconstrained · MANE · 132 kb · p 0.046 · regional, not allelic
Overall
CADD	21.6	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 0.00297% European (non-Finnish) · 35/1,179,940 alleles

Filtering AF 0.00215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00217% 35/1,612,820 alleles · very rare exomes 31/1,460,596 · genomes 4/152,224 · joint denominator

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: LAMA4
Protein: p.Trp14Arg
Coding: c.40T>C
MANE Select: NM_001105206
dbSNP: rs782293373
Type: single nucleotide variant
Location: chr6:112254111 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.75

Full LAMA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1JJ

Similar variants

LAMA4 c.1077+4C>T Uncertain significance ★★ same condition
LAMA4 c.1077+5G>A Uncertain significance ★★ same condition
LAMA4 c.1357+1G>A Uncertain significance ★★ same condition
LAMA4 c.3283-3C>G Uncertain significance ★★ same condition
LAMA4 c.3557+4A>G Uncertain significance ★★ same condition
LAMA4 c.3697-3C>T Uncertain significance ★★ same condition
LAMA4 c.4666-3C>T Uncertain significance ★★ same condition
LAMA4 c.5206+1G>A 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/lama4-p-trp14arg (accessed [today's date]).

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