Is L1CAM p.Ala1237Val (c.3710C>T) pathogenic?

L1CAM p.Ala1237Val (c.3710C>T) is classified Benign/Likely benign in L1CAM (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0886); Very rare (popmax 0.00351%, sas); Associated with Spastic paraplegia.

What condition is associated with L1CAM p.Ala1237Val (c.3710C>T)?

L1CAM p.Ala1237Val (c.3710C>T) is associated with Spastic paraplegia (ClinVar).

How common is L1CAM p.Ala1237Val (c.3710C>T) in the general population?

L1CAM p.Ala1237Val (c.3710C>T) is very rare (popmax 0.00351%, sas) (gnomAD).

What do computational predictors say about L1CAM p.Ala1237Val (c.3710C>T)?

AlphaMissense predicts likely benign (score 0.0886) — an in-silico prediction, not a clinical call.

L1CAM p.Ala1237Val

c.3710C>T · rs370546591 · VCV1050405

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0886 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00351%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.0886	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -7.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -3.7, phastCons 0.84
Regional constraint	o/e 0.78	unconstrained · MANE · 1,700 bp · p 0.0077 · regional, not allelic
Overall
CADD	11.43	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 0.00351% South Asian · 2/56,937 alleles

Filtering AF 0.000715% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000565%

Overall 0.00339% 41/1,210,824 alleles · very rare exomes 33/1,097,935 · genomes 8/112,889 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0998%	1,002
Remaining individualsnot grpmax-eligible	0.0042%	23,799
South Asiangrpmax	0.00351%	28,469
East Asian	0.00296%	33,775
Finnishnot grpmax-eligible	0.00214%	46,779
African / African-American	0.00174%	57,507
European (non-Finnish)	0.00134%	74,597

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: L1CAM
Protein: p.Ala1237Val
Coding: c.3710C>T
MANE Select: NM_001278116
dbSNP: rs370546591
Type: single nucleotide variant
Location: chrX:153862727 (GRCh38)
Structure: AlphaFold pLDDT 78.82 · 2 PDB
Residue 1237: a UniProt-annotated variant site (found in l1 syndrome; likely pathogenic); the 'disordered' region

Full L1CAM gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

L1CAM p.Ala1237= Likely benign ★★ same residue
L1CAM c.2431+5G>A Pathogenic/Likely pathogenic ★★ same condition
L1CAM c.2872+1G>A Pathogenic ★★ same condition
L1CAM c.3531-12G>A Pathogenic/Likely pathogenic ★★ same condition
L1CAM c.400+5G>A Pathogenic/Likely pathogenic ★★ same condition
L1CAM c.806+1G>C Pathogenic ★★ same condition
L1CAM c.807-6G>A Pathogenic/Likely pathogenic ★★ same condition
L1CAM c.92-1G>A Pathogenic/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/l1cam-p-ala1237val (accessed [today's date]).

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