Is LINS1 p.Ile541Val (c.1621A>G) pathogenic?

LINS1 p.Ile541Val (c.1621A>G) is classified Benign in LINS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-06-09). AlphaMissense: likely benign (0.0672); Common (popmax 19.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Inborn genetic diseases.

What condition is associated with LINS1 p.Ile541Val (c.1621A>G)?

LINS1 p.Ile541Val (c.1621A>G) is associated with Inborn genetic diseases (ClinVar).

What do computational predictors say about LINS1 p.Ile541Val (c.1621A>G)?

AlphaMissense predicts likely benign (score 0.0672) — an in-silico prediction, not a clinical call.

LINS1 p.Ile541Val

Q: How common is LINS1 p.Ile541Val (c.1621A>G) in the general population?

LINS1 p.Ile541Val (c.1621A>G) is common (popmax 19.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1621A>G · rs12915007 · VCV587885

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0672 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 19.5%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0672	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -5.09	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 -1.7	GERP -5.1
Regional constraint	o/e 1.08	unconstrained · MANE · 12 kb · p 0.017 · regional, not allelic
Overall
CADD	1.764	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 19.5% East Asian · 8,751/44,864 alleles

Filtering AF 19.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 19%

Overall 2.26% 36,418/1,612,564 alleles · common exomes 31,063/1,460,294 · genomes 5,355/152,270 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	19.5%	5
Admixed American	8.8%	11
Middle Eastern	4.21%	24
African / African-American	3.81%	26
Remaining individualsnot grpmax-eligible	3.13%	32
Ashkenazi Jewishnot grpmax-eligible	2.62%	38
Finnishnot grpmax-eligible	2.54%	39
South Asian	2.33%	43
Amishnot grpmax-eligible	1.32%	76
European (non-Finnish)	1.09%	92

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.Ile541Val
Coding: c.1621A>G
MANE Select: NM_001040616
dbSNP: rs12915007
Type: single nucleotide variant
Location: chr15:100569891 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 541: a UniProt-annotated variant site (in)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LINS1 c.1394+4A>G Uncertain significance ★★ same condition
LINS1 p.Ala338Val Uncertain significance ★★ ⚠ same condition
LINS1 p.Asn433Ser Uncertain significance ★★ ⚠ same condition
LINS1 p.Asp630Asn Uncertain significance ★★ ⚠ same condition
LINS1 p.Ile494Thr Uncertain significance ★★ ⚠ same condition
LINS1 p.Leu757Ter Uncertain significance ★★ same condition
LINS1 p.Met449Ile Uncertain significance ★★ ⚠ same condition
LINS1 p.Ala331Val Benign ★★ 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/lins1-p-ile541val (accessed [today's date]).

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