Is SMAD6 p.Trp14fs (c.39_40del) pathogenic?

SMAD6 p.Trp14fs (c.3940del) is classified Likely pathogenic in SMAD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-02). No gnomAD frequency available for this variant.

How common is SMAD6 p.Trp14fs (c.39_40del) in the general population?

SMAD6 p.Trp14fs (c.39_40del) is no gnomAD frequency available for this variant (gnomAD).

SMAD6 p.Trp14fs

c.39_40del · rs2545310277 · VCV2507219

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 4
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.4	GERP 1.4, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SMAD6
Protein: p.Trp14fs
Coding: c.39_40del
MANE Select: NM_005585
dbSNP: rs2545310277
Type: Deletion
Location: chr15:66703296 (GRCh38)
Gene constraint: LOEUF 1.996 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.34
Residue 14: a UniProt-annotated variant site (in aovd2); a UniProt-annotated variant site (in crs7; uncertain significance; no effect on inhibition of bmp signaling pathway); the 'disordered' region

Full SMAD6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SMAD6 p.Trp14Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
SMAD6 p.Trp14Cys Uncertain significance ★ ⚠ same residue
SMAD6 p.Trp14Gly Uncertain significance ★ ⚠ same residue
SMAD6 p.Trp14Ter Conflicting classifications of pathogenicity ★ same residue
SMAD6 p.Gln78fs Pathogenic/Likely pathogenic ★★ same type
SMAD6 c.806_817+19del Uncertain significance ★★ same type
SMAD6 p.Asp295_Ser296del Uncertain significance ★★ same type
SMAD6 p.Pro90fs Uncertain significance ★★ 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/smad6-p-trp14fs (accessed [today's date]).

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