Is SAMD9 p.Arg221= (c.663A>G) pathogenic?

SAMD9 p.Arg221= (c.663A>G) is classified Likely benign in SAMD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-26). Absent from gnomAD v4.1.

How common is SAMD9 p.Arg221= (c.663A>G) in the general population?

SAMD9 p.Arg221= (c.663A>G) is absent from gnomAD v4.1 (gnomAD).

SAMD9 p.Arg221=

c.663A>G · VCV4896757

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.055	GERP 0.56, phastCons 0.005
Overall
CADD	8.22	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SAMD9
Protein: p.Arg221=
Coding: c.663A>G
MANE Select: NM_017654
Type: single nucleotide variant
Location: chr7:93105435 (GRCh38)
Gene constraint: LOEUF 1.773 · pLI 0.03 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 83.79 · 10 PDB
Residue 221: an α-helix

Full SAMD9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SAMD9 p.Arg221Ter Uncertain significance ★★ same residue
SAMD9 p.Arg221Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
SAMD9 p.Arg221Leu Uncertain significance ★ ⚠ same residue
SAMD9 p.Arg221_Phe222insAsnGluValPheArg Uncertain significance ★ same residue
SAMD9 p.Arg1293Trp Pathogenic ★★ ⚠ same type
SAMD9 p.Arg459Gln Pathogenic ★★ ⚠ same type
SAMD9 p.Arg685Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
SAMD9 p.Arg824Gln Pathogenic ★★ ⚠ 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/samd9-p-arg221 (accessed [today's date]).

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