Is SAMD9 p.Arg75Trp (c.223C>T) pathogenic?

SAMD9 p.Arg75Trp (c.223C>T) is classified Benign/Likely benign in SAMD9 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0966); Low-frequency (popmax 4.75%, sas).

How common is SAMD9 p.Arg75Trp (c.223C>T) in the general population?

SAMD9 p.Arg75Trp (c.223C>T) is low-frequency (popmax 4.75%, sas) (gnomAD).

What do computational predictors say about SAMD9 p.Arg75Trp (c.223C>T)?

AlphaMissense predicts likely benign (score 0.0966) — an in-silico prediction, not a clinical call.

SAMD9 p.Arg75Trp

c.223C>T · rs111780648 · VCV1049816

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0966 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.75%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0966	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -8.25	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 -0.034	GERP 0.099
Regional constraint	o/e 1.09	unconstrained · MANE · 1,176 bp · p 0.058 · regional, not allelic
Overall
CADD	16.62	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.75% South Asian · 4,324/91,074 alleles

Filtering AF 4.63% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.58%

Overall 2.16% 34,875/1,613,970 alleles · low-frequency exomes 32,367/1,461,764 · genomes 2,508/152,206 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	4.75%	21
Middle Eastern	3.18%	31
European (non-Finnish)	2.26%	44
Remaining individualsnot grpmax-eligible	2.18%	46
Ashkenazi Jewishnot grpmax-eligible	1.91%	52
Admixed American	1.42%	70
Finnishnot grpmax-eligible	1.07%	94
African / African-American	0.321%	311
Amishnot grpmax-eligible	0.11%	912
East Asian	0.0111%	8,972

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.Arg75Trp
Coding: c.223C>T
MANE Select: NM_017654
dbSNP: rs111780648
Type: single nucleotide variant
Location: chr7:93105875 (GRCh38)
Gene constraint: LOEUF 1.773 · pLI 0.03 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 83.79 · 10 PDB
Residue 75: the sam domain

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

Similar variants

SAMD9 p.Arg75= Likely benign ★★ same residue
SAMD9 p.Arg75Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
SAMD9 p.Arg75fs 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
SAMD9 p.Arg982Cys Pathogenic/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-arg75trp (accessed [today's date]).

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