Is SMAD6 p.Pro20Ser (c.58C>T) pathogenic?

SMAD6 p.Pro20Ser (c.58C>T) is classified Uncertain significance in SMAD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-12). AlphaMissense: likely benign (0.2805); No allele count reported in gnomAD v4.1 (AN 1,487,444); Associated with Inborn genetic diseases.

What condition is associated with SMAD6 p.Pro20Ser (c.58C>T)?

SMAD6 p.Pro20Ser (c.58C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SMAD6 p.Pro20Ser (c.58C>T) in the general population?

SMAD6 p.Pro20Ser (c.58C>T) is no allele count reported in gnomAD v4.1 (AN 1,487,444) (gnomAD).

What do computational predictors say about SMAD6 p.Pro20Ser (c.58C>T)?

AlphaMissense predicts likely benign (score 0.2805) — an in-silico prediction, not a clinical call.

SMAD6 p.Pro20Ser

c.58C>T · VCV4631612

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2805 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,487,444)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2805	likely benign
REVEL	0.212	benign-leaning
SaProt	LLR -5.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.6	GERP 1.2, phastCons 1
Regional constraint	o/e 1.49	unconstrained · MANE · 78 kb · p 4.6e-40 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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 1,487,444). 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.Pro20Ser
Coding: c.58C>T
MANE Select: NM_005585
Type: single nucleotide variant
Location: chr15:66703316 (GRCh38)
Gene constraint: LOEUF 1.996 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.34
Residue 20: a UniProt-annotated variant site (in aovd2); the 'disordered' region

Full SMAD6 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

SMAD6 p.Pro20Leu Uncertain significance ★ ⚠ same residue
SMAD6 p.Ala100Pro Uncertain significance ★★ ⚠ same condition
SMAD6 p.Ala100Thr Uncertain significance ★★ ⚠ same condition
SMAD6 p.Ala134Thr Uncertain significance ★★ ⚠ same condition
SMAD6 p.Ala135Thr Uncertain significance ★★ ⚠ same condition
SMAD6 p.Ala211Val Uncertain significance ★★ ⚠ same condition
SMAD6 p.Ala253Thr Uncertain significance ★★ ⚠ same condition
SMAD6 p.Ala424Val Uncertain significance ★★ ⚠ 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/smad6-p-pro20ser (accessed [today's date]).

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