Is ADD3 p.Ser180fs (c.537_540del) pathogenic?

ADD3 p.Ser180fs (c.537540del) is classified Uncertain significance in ADD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-30). Very rare (popmax 8.51e-05%, nfe).

How common is ADD3 p.Ser180fs (c.537_540del) in the general population?

ADD3 p.Ser180fs (c.537_540del) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

ADD3 p.Ser180fs

c.537_540del · VCV4700315

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 8.51e-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 5 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.005	GERP -1.1, phastCons 0.79

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.51e-05% European (non-Finnish) · 1/1,174,640 alleles

Overall 6.87e-05% 1/1,455,634 alleles · very rare

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: ADD3
Protein: p.Ser180fs
Coding: c.537_540del
MANE Select: NM_016824
Type: Deletion
Location: chr10:110117390 (GRCh38)
Gene constraint: LOEUF 0.395 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.83

Full ADD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADD3 p.Glu559del Uncertain significance ★★ same type
ADD3 p.Lys701del Uncertain significance ★ same type
ADD3 c.1733-12del Likely benign ★ same type
ADD3 c.335-11del 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/add3-p-ser180fs (accessed [today's date]).

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