Is LINS1 p.Ser674fs (c.2020dup) pathogenic?

LINS1 p.Ser674fs (c.2020dup) is classified Likely pathogenic in LINS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-26). Very rare (popmax 0.00364%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LINS1 p.Ser674fs (c.2020dup)?

LINS1 p.Ser674fs (c.2020dup) is associated with Inborn genetic diseases (ClinVar).

How common is LINS1 p.Ser674fs (c.2020dup) in the general population?

LINS1 p.Ser674fs (c.2020dup) is very rare (popmax 0.00364%, nfe) (gnomAD).

LINS1 p.Ser674fs

c.2020dup · rs1261920708 · VCV985554

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00364%, nfe)

Conditions

Inborn genetic diseases

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 0.039	GERP -2.5
Overall
CADD	22.5	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 0.00364% European (non-Finnish) · 43/1,180,038 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00266% 43/1,614,040 alleles · very rare exomes 41/1,461,888 · genomes 2/152,152 · 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.Ser674fs
Coding: c.2020dup
MANE Select: NM_001040616
dbSNP: rs1261920708
Type: Duplication
Location: chr15:100569491 (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

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-ser674fs (accessed [today's date]).

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