Is LINS1 p.Ser594fs (c.1780dup) pathogenic?

LINS1 p.Ser594fs (c.1780dup) is classified Uncertain significance in LINS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-01-05). Very rare (popmax 0.00134%, afr).

How common is LINS1 p.Ser594fs (c.1780dup) in the general population?

LINS1 p.Ser594fs (c.1780dup) is very rare (popmax 0.00134%, afr) (gnomAD).

LINS1 p.Ser594fs

c.1780dup · rs1276656996 · VCV499706

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (7 of 7) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.6	GERP -0.23, phastCons 0.65
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,898 alleles

Overall 6.2e-05% 1/1,613,728 alleles · very rare exomes 0/1,461,554 · genomes 1/152,174 · joint denominator

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.Ser594fs
Coding: c.1780dup
MANE Select: NM_001040616
dbSNP: rs1276656996
Type: Duplication
Location: chr15:100569731 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44

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

Similar variants

LINS1 p.Ser674fs Likely pathogenic ★★ same type
LINS1 p.Arg383fs Likely pathogenic ★ same type
LINS1 p.Arg621fs Likely pathogenic ★ same type
LINS1 p.Gln115fs Pathogenic ★ same type
LINS1 p.Ile556fs Uncertain significance ★ same type
LINS1 p.Ser625fs Conflicting classifications of pathogenicity ★ same type
LINS1 p.Thr52fs Uncertain significance ★ same type
LINS1 c.1222+142dup Benign ★ 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-ser594fs (accessed [today's date]).

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