Is LAMA4 p.Ser1663Phe (c.4988C>T) pathogenic?

LAMA4 p.Ser1663Phe (c.4988C>T) is classified Uncertain significance in LAMA4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-17). AlphaMissense: ambiguous (0.4543); Very rare (popmax 0.00533%, afr); Associated with Cardiovascular phenotype.

What condition is associated with LAMA4 p.Ser1663Phe (c.4988C>T)?

LAMA4 p.Ser1663Phe (c.4988C>T) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1JJ (ClinVar).

How common is LAMA4 p.Ser1663Phe (c.4988C>T) in the general population?

LAMA4 p.Ser1663Phe (c.4988C>T) is very rare (popmax 0.00533%, afr) (gnomAD).

What do computational predictors say about LAMA4 p.Ser1663Phe (c.4988C>T)?

AlphaMissense predicts ambiguous (score 0.4543) — an in-silico prediction, not a clinical call.

LAMA4 p.Ser1663Phe

c.4988C>T · rs200238782 · VCV1910924

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4543 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4543	ambiguous
REVEL	0.767	pathogenic-leaning
SaProt	LLR -8.28	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 13 kb · p 0.0088 · regional, not allelic
Overall
CADD	29.3	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 0.00533% African / African-American · 4/74,988 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,612,760 alleles · very rare exomes 2/1,460,432 · genomes 2/152,328 · 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.Ser1663Phe
Coding: c.4988C>T
MANE Select: NM_001105206
dbSNP: rs200238782
Type: single nucleotide variant
Location: chr6:112115987 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.75
Residue 1663: the laminin g-like 5 domain

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-ser1663phe (accessed [today's date]).

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