Is EXTL3 p.Arg660fs (c.1978del) pathogenic?

EXTL3 p.Arg660fs (c.1978del) is classified Uncertain significance in EXTL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). Very rare (popmax 8.48e-05%, nfe).

How common is EXTL3 p.Arg660fs (c.1978del) in the general population?

EXTL3 p.Arg660fs (c.1978del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

EXTL3 p.Arg660fs

c.1978del · rs2130742237 · VCV1347541

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 8.48e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 3 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.54	GERP -3.9, phastCons 0.033

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,810 alleles

Overall 6.2e-05% 1/1,613,440 alleles · very rare exomes 1/1,461,892 · genomes 0/151,548 · 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: EXTL3
Protein: p.Arg660fs
Coding: c.1978del
MANE Select: NM_001440
dbSNP: rs2130742237
Type: Deletion
Location: chr8:28718034 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 84.22 · 4 PDB

Full EXTL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EXTL3 p.Arg660Gln Uncertain significance ★★ ⚠ same residue
EXTL3 p.Arg660Ter Uncertain significance ★ same residue
EXTL3 p.Asn290_Arg295del Uncertain significance ★ same type
EXTL3 p.Pro554del Uncertain significance ★ same type
EXTL3 c.2277-5del 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/extl3-p-arg660fs (accessed [today's date]).

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