Is SMAD6 p.Trp14Arg (c.40T>A) pathogenic?

SMAD6 p.Trp14Arg (c.40T>A) is classified Conflicting classifications of pathogenicity in SMAD6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-08). AlphaMissense: likely pathogenic (0.999); No allele count reported in gnomAD v4.1 (AN 1,491,768).

How common is SMAD6 p.Trp14Arg (c.40T>A) in the general population?

SMAD6 p.Trp14Arg (c.40T>A) is no allele count reported in gnomAD v4.1 (AN 1,491,768) (gnomAD).

What do computational predictors say about SMAD6 p.Trp14Arg (c.40T>A)?

AlphaMissense predicts likely pathogenic (score 0.999) — an in-silico prediction, not a clinical call.

SMAD6 p.Trp14Arg

c.40T>A · rs1353173742 · VCV1879296

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.999 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,491,768)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.999	likely pathogenic · top 4% in SMAD6
REVEL	0.647	pathogenic-leaning
SaProt	LLR -10.62	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.49	unconstrained · MANE · 78 kb · p 4.6e-40 · regional, not allelic
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,491,768). 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.Trp14Arg
Coding: c.40T>A
MANE Select: NM_005585
dbSNP: rs1353173742
Type: single nucleotide variant
Location: chr15:66703298 (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.Trp14Cys Uncertain significance ★ ⚠ same residue
SMAD6 p.Trp14Gly Uncertain significance ★ ⚠ same residue
SMAD6 p.Trp14Ter Conflicting classifications of pathogenicity ★ same residue
SMAD6 p.Trp14fs Likely pathogenic ★ same residue
SMAD6 p.Gln218Ter Pathogenic/Likely pathogenic ★★ same type
SMAD6 p.Gln370Ter Likely pathogenic ★★ same type
SMAD6 p.Tyr264Ter Pathogenic/Likely pathogenic ★★ same type
SMAD6 c.817+4A>G 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-trp14arg (accessed [today's date]).

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