Is SAMD9 p.Arg459Ter (c.1375C>T) pathogenic?

SAMD9 p.Arg459Ter (c.1375C>T) is classified Uncertain significance in SAMD9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-15). Very rare (popmax 0.00797%, nfe).

How common is SAMD9 p.Arg459Ter (c.1375C>T) in the general population?

SAMD9 p.Arg459Ter (c.1375C>T) is very rare (popmax 0.00797%, nfe) (gnomAD).

SAMD9 p.Arg459Ter

c.1375C>T · rs145018604 · VCV1479131

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00797%, nfe)

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 0.69	phastCons 0.001
Overall
CADD	36.0	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 0.00797% European (non-Finnish) · 94/1,179,930 alleles

Filtering AF 0.00664% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00616%

Overall 0.00601% 97/1,613,774 alleles · very rare exomes 86/1,461,700 · genomes 11/152,074 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00797%	12,552
African / African-American	0.00267%	37,447
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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.Arg459Ter
Coding: c.1375C>T
MANE Select: NM_017654
dbSNP: rs145018604
Type: single nucleotide variant
Location: chr7:93104723 (GRCh38)
Gene constraint: LOEUF 1.773 · pLI 0.03 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 83.79 · 10 PDB
Residue 459: a UniProt-annotated variant site (in mirage; decreased cell proliferation; changed endosome organization)

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

Similar variants

SAMD9 p.Arg459Gln Pathogenic ★★ ⚠ same residue
SAMD9 p.Arg459= Likely benign ★ same residue
SAMD9 p.Arg1293Trp Pathogenic ★★ ⚠ same type
SAMD9 p.Arg685Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
SAMD9 p.Arg824Gln Pathogenic ★★ ⚠ same type
SAMD9 p.Arg982Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
SAMD9 p.Arg982His Pathogenic/Likely pathogenic ★★ ⚠ same type
SAMD9 p.Leu1511Ser Likely 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-arg459ter (accessed [today's date]).

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