Is SAMD9 p.Arg221Ter (c.661C>T) pathogenic?

SAMD9 p.Arg221Ter (c.661C>T) is classified Uncertain significance in SAMD9 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-05). Very rare (popmax 0.00935%, afr).

How common is SAMD9 p.Arg221Ter (c.661C>T) in the general population?

SAMD9 p.Arg221Ter (c.661C>T) is very rare (popmax 0.00935%, afr) (gnomAD).

SAMD9 p.Arg221Ter

c.661C>T · rs778654614 · VCV2078553

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.096	GERP -2.1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00935% African / African-American · 7/74,878 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.0018% 29/1,613,838 alleles · very rare exomes 27/1,461,820 · genomes 2/152,018 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,697
South Asian	0.00769%	13,011
Admixed American	0.005%	19,998
East Asian	0.00446%	22,434
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000763%	131,108

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: SAMD9
Protein: p.Arg221Ter
Coding: c.661C>T
MANE Select: NM_017654
dbSNP: rs778654614
Type: single nucleotide variant
Location: chr7:93105437 (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.Arg221Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
SAMD9 p.Arg221Leu Uncertain significance ★ ⚠ same residue
SAMD9 p.Arg221= Likely benign ★ 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-arg221ter (accessed [today's date]).

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