Is LINS1 p.Val406Met (c.1216G>A) pathogenic?

LINS1 p.Val406Met (c.1216G>A) is classified Benign in LINS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-27). AlphaMissense: likely benign (0.058); Common (popmax 99.6%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about LINS1 p.Val406Met (c.1216G>A)?

AlphaMissense predicts likely benign (score 0.058) — an in-silico prediction, not a clinical call.

LINS1 p.Val406Met

Q: How common is LINS1 p.Val406Met (c.1216G>A) in the general population?

LINS1 p.Val406Met (c.1216G>A) is common (popmax 99.6%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1216G>A · VCV4926832

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.058 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 99.6%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.058	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -4.47	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 1.2	GERP 0.62, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 12 kb · p 0.017 · regional, not allelic
Overall
CADD	14.1	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 99.6% European (non-Finnish) · 1,149,223/1,154,034 alleles

Filtering AF 99.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.4%

Overall 97.8% 1,549,094/1,583,140 alleles · common exomes 1,401,867/1,430,802 · genomes 147,227/152,338 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	100%	1
European (non-Finnish)grpmax	99.6%	1
Middle Eastern	99.4%	1
Finnishnot grpmax-eligible	98.6%	1
Admixed American	97%	1
Remaining individualsnot grpmax-eligible	96.7%	1
South Asian	96.2%	1
African / African-American	95.3%	1
Ashkenazi Jewishnot grpmax-eligible	95%	1
East Asian	63.8%	2

Amish 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: LINS1
Protein: p.Val406Met
Coding: c.1216G>A
MANE Select: NM_001040616
Type: single nucleotide variant
Location: chr15:100573657 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 406: a UniProt-annotated variant site (in)

Full LINS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LINS1 p.Val406= Benign ★ same residue
LINS1 p.Leu393Ter Pathogenic/Likely pathogenic ★★ same type
LINS1 c.1394+4A>G Uncertain significance ★★ same type
LINS1 p.Ala338Val Uncertain significance ★★ ⚠ same type
LINS1 p.Asn433Ser Uncertain significance ★★ ⚠ same type
LINS1 p.Asp221Asn Uncertain significance ★★ ⚠ same type
LINS1 p.Asp630Asn Uncertain significance ★★ ⚠ same type
LINS1 p.Ile494Thr 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/lins1-p-val406met (accessed [today's date]).

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