Is SAMD9 p.Phe1217Ser (c.3650T>C) pathogenic?

SAMD9 p.Phe1217Ser (c.3650T>C) is classified Uncertain significance in SAMD9 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-04). AlphaMissense: likely pathogenic (0.796); Very rare (popmax 0.00668%, afr); Associated with Inborn genetic diseases.

What condition is associated with SAMD9 p.Phe1217Ser (c.3650T>C)?

SAMD9 p.Phe1217Ser (c.3650T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SAMD9 p.Phe1217Ser (c.3650T>C) in the general population?

SAMD9 p.Phe1217Ser (c.3650T>C) is very rare (popmax 0.00668%, afr) (gnomAD).

What do computational predictors say about SAMD9 p.Phe1217Ser (c.3650T>C)?

AlphaMissense predicts likely pathogenic (score 0.796) — an in-silico prediction, not a clinical call.

SAMD9 p.Phe1217Ser

c.3650T>C · VCV3713532

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.796 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.796	likely pathogenic · top 10% in SAMD9
REVEL	0.359	indeterminate
SaProt	LLR -6.77	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 2,122 bp · p 6.9e-06 · regional, not allelic
Overall
CADD	23.8	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 0.00668% African / African-American · 5/74,892 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.000558% 9/1,613,612 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00668%	14,978
Remaining individualsnot grpmax-eligible	0.0032%	31,235
European (non-Finnish)	0.00017%	589,863

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.Phe1217Ser
Coding: c.3650T>C
MANE Select: NM_017654
Type: single nucleotide variant
Location: chr7:93102448 (GRCh38)
Gene constraint: LOEUF 1.773 · pLI 0.03 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 83.79 · 10 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SAMD9 p.Phe1217Leu Uncertain significance ★★ ⚠ same residue
SAMD9 p.Phe1217= Likely benign ★ same residue
SAMD9 p.Ala1057Val Uncertain significance ★★ ⚠ same condition
SAMD9 p.Ala1066Thr Uncertain significance ★★ ⚠ same condition
SAMD9 p.Ala1069Thr Uncertain significance ★★ ⚠ same condition
SAMD9 p.Ala1082Gly Uncertain significance ★★ ⚠ same condition
SAMD9 p.Ala1102Asp Uncertain significance ★★ ⚠ same condition
SAMD9 p.Ala1195Asp Uncertain significance ★★ ⚠ same condition

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-phe1217ser (accessed [today's date]).

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