Is SMAD6 p.Arg22Pro (c.65G>C) pathogenic?

SMAD6 p.Arg22Pro (c.65G>C) is classified Uncertain significance in SMAD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-29). AlphaMissense: likely benign (0.1356); Very rare (popmax 0.00257%, sas).

How common is SMAD6 p.Arg22Pro (c.65G>C) in the general population?

SMAD6 p.Arg22Pro (c.65G>C) is very rare (popmax 0.00257%, sas) (gnomAD).

What do computational predictors say about SMAD6 p.Arg22Pro (c.65G>C)?

AlphaMissense predicts likely benign (score 0.1356) — an in-silico prediction, not a clinical call.

SMAD6 p.Arg22Pro

c.65G>C · VCV3373086

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1356 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00257%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1356	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -5.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -0.018, phastCons 1
Regional constraint	o/e 1.49	unconstrained · MANE · 78 kb · p 4.6e-40 · regional, not allelic
Overall
CADD	19.07	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

Grpmax group 0.00257% South Asian · 2/77,822 alleles

Filtering AF 0.000427% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00016%

Overall 0.000202% 3/1,486,682 alleles · very rare exomes 3/1,334,570 · genomes 0/152,112 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00257%	38,911
European (non-Finnish)	8.95e-05%	1,117,209

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: SMAD6
Protein: p.Arg22Pro
Coding: c.65G>C
MANE Select: NM_005585
Type: single nucleotide variant
Location: chr15:66703323 (GRCh38)
Gene constraint: LOEUF 1.996 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.34
Residue 22: a UniProt-annotated variant site (in aovd2); the 'disordered' region

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

Similar variants

SMAD6 p.Arg22Gln Uncertain significance ★ ⚠ same residue
SMAD6 p.Arg22Trp Uncertain significance ★ ⚠ 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
SMAD6 p.Ala100Pro Uncertain significance ★★ ⚠ same type
SMAD6 p.Ala100Thr 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-arg22pro (accessed [today's date]).

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