Is LAMC3 p.Ala1237Thr (c.3709G>A) pathogenic?

LAMC3 p.Ala1237Thr (c.3709G>A) is classified Uncertain significance in LAMC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-15). AlphaMissense: likely benign (0.0754); Ultra-rare (popmax 0.0134%, eas).

How common is LAMC3 p.Ala1237Thr (c.3709G>A) in the general population?

LAMC3 p.Ala1237Thr (c.3709G>A) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about LAMC3 p.Ala1237Thr (c.3709G>A)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

LAMC3 p.Ala1237Thr

c.3709G>A · rs759159746 · VCV1412989

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -7.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.1	GERP -0.57, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 83 kb · p 0.0039 · regional, not allelic
Overall
CADD	11.76	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,888 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.000434% 7/1,613,882 alleles · ultra-rare exomes 6/1,461,718 · genomes 1/152,164 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,481
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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: LAMC3
Protein: p.Ala1237Thr
Coding: c.3709G>A
MANE Select: NM_006059
dbSNP: rs759159746
Type: single nucleotide variant
Location: chr9:131077266 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.23
Residue 1237: the 'domain ii and i' region

Full LAMC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LAMC3 c.1166-1G>A Likely pathogenic ★★ same type
LAMC3 c.3211+1G>A Likely pathogenic ★★ same type
LAMC3 c.3211+2T>C Likely pathogenic ★★ same type
LAMC3 c.976+1G>A Pathogenic ★★ same type
LAMC3 p.Cys810Ter Pathogenic ★★ same type
LAMC3 p.Gln550Ter Pathogenic ★★ same type
LAMC3 p.Ser421Ter Pathogenic ★★ same type
LAMC3 p.Ala1090Ser 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/lamc3-p-ala1237thr (accessed [today's date]).

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