Is LINGO4 p.Arg421Gln (c.1262G>A) pathogenic?

LINGO4 p.Arg421Gln (c.1262G>A) is classified Uncertain significance in LINGO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-09-01). AlphaMissense: likely benign (0.0984); Ultra-rare (popmax 0.0321%, nfe); Associated with polymicrogyria.

What condition is associated with LINGO4 p.Arg421Gln (c.1262G>A)?

LINGO4 p.Arg421Gln (c.1262G>A) is associated with polymicrogyria (ClinVar).

How common is LINGO4 p.Arg421Gln (c.1262G>A) in the general population?

LINGO4 p.Arg421Gln (c.1262G>A) is ultra-rare (popmax 0.0321%, nfe) (gnomAD).

What do computational predictors say about LINGO4 p.Arg421Gln (c.1262G>A)?

AlphaMissense predicts likely benign (score 0.0984) — an in-silico prediction, not a clinical call.

LINGO4 p.Arg421Gln

c.1262G>A · rs143154971 · VCV438603

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0984 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0321%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

polymicrogyria

Computational evidence

Protein change
AlphaMissense	0.0984	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -6.49	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 5.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 1,778 bp · p 0.22 · regional, not allelic
Overall
CADD	19.53	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 0.0321% European (non-Finnish) · 379/1,180,052 alleles

Filtering AF 0.0294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0283%

Overall 0.0245% 396/1,614,024 alleles · ultra-rare exomes 381/1,461,784 · genomes 15/152,240 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0321%	3,114
Remaining individualsnot grpmax-eligible	0.0224%	4,463
Admixed American	0.00167%	60,018
African / African-American	0.00133%	74,952
South Asian	0.0011%	91,094

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: LINGO4
Protein: p.Arg421Gln
Coding: c.1262G>A
MANE Select: NM_001004432
dbSNP: rs143154971
Type: single nucleotide variant
Location: chr1:151801443 (GRCh38)
Gene constraint: LOEUF 1.137 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.70
Residue 421: the ig-like c2-type domain

Full LINGO4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

LINGO4 p.Ser284Phe Conflicting classifications of pathogenicity ★ ⚠ same condition
LINGO4 p.Ala151Val Uncertain significance ★ ⚠ same type
LINGO4 p.Ala223Asp Uncertain significance ★ ⚠ same type
LINGO4 p.Ala223Thr Uncertain significance ★ ⚠ same type
LINGO4 p.Ala319Thr Uncertain significance ★ same type
LINGO4 p.Ala335Thr Uncertain significance ★ ⚠ same type
LINGO4 p.Ala431Val Uncertain significance ★ ⚠ same type
LINGO4 p.Ala442Thr 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/lingo4-p-arg421gln (accessed [today's date]).

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