Is LAMA2 p.Leu685Pro (c.2054T>C) pathogenic?

LAMA2 p.Leu685Pro (c.2054T>C) is classified Uncertain significance in LAMA2 (ClinVar, Single submitter, 2 submitters; last evaluated 2017-09-13). AlphaMissense: likely pathogenic (0.9328); Absent from gnomAD v4.1; Associated with congenital merosin-deficient muscular dystrophy 1A.

What condition is associated with LAMA2 p.Leu685Pro (c.2054T>C)?

LAMA2 p.Leu685Pro (c.2054T>C) is associated with congenital merosin-deficient muscular dystrophy 1A (ClinVar).

How common is LAMA2 p.Leu685Pro (c.2054T>C) in the general population?

LAMA2 p.Leu685Pro (c.2054T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LAMA2 p.Leu685Pro (c.2054T>C)?

AlphaMissense predicts likely pathogenic (score 0.9328) — an in-silico prediction, not a clinical call.

LAMA2 p.Leu685Pro

c.2054T>C · rs746641607 · VCV451986

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9328 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

congenital merosin-deficient muscular dystrophy 1A

Computational evidence

Protein change
AlphaMissense	0.9328	likely pathogenic
REVEL	0.681	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 351 kb · p 0.83 · regional, not allelic
Overall
CADD	27.2	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 is an independent agreement signal.

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: LAMA2
Protein: p.Leu685Pro
Coding: c.2054T>C
MANE Select: NM_000426
dbSNP: rs746641607
Type: single nucleotide variant
Location: chr6:129252253 (GRCh38)
Gene constraint: LOEUF 0.801 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 685: a UniProt-annotated variant site (in mdc1a); a UniProt-annotated variant site (in lgmdr23); the laminin iv type a 1 domain

Full LAMA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital merosin-deficient muscular dystrophy 1A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LAMA2 p.Leu685Arg Uncertain significance ★★ same residue
LAMA2 p.Leu685Val Uncertain significance ★ ⚠ same residue
LAMA2 c.1028-1G>A Likely pathogenic ★★ same condition
LAMA2 c.112+1G>A Pathogenic/Likely pathogenic ★★ same condition
LAMA2 c.112+2T>C Pathogenic ★★ same condition
LAMA2 c.1306+2T>G Pathogenic/Likely pathogenic ★★ same condition
LAMA2 c.1467+2T>C Pathogenic/Likely pathogenic ★★ same condition
LAMA2 c.1884+2T>C Likely pathogenic ★★ 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/lama2-p-leu685pro (accessed [today's date]).

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