Is SAMD9 p.Phe222Ile (c.664T>A) pathogenic?

SAMD9 p.Phe222Ile (c.664T>A) is classified Uncertain significance in SAMD9 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.8243); Very rare (popmax 0.0022%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SAMD9 p.Phe222Ile (c.664T>A)?

SAMD9 p.Phe222Ile (c.664T>A) is associated with Inborn genetic diseases (ClinVar).

How common is SAMD9 p.Phe222Ile (c.664T>A) in the general population?

SAMD9 p.Phe222Ile (c.664T>A) is very rare (popmax 0.0022%, nfe) (gnomAD).

What do computational predictors say about SAMD9 p.Phe222Ile (c.664T>A)?

AlphaMissense predicts likely pathogenic (score 0.8243) — an in-silico prediction, not a clinical call.

SAMD9 p.Phe222Ile

c.664T>A · rs201875833 · VCV1491433

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8243 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8243	likely pathogenic · top 9% in SAMD9
REVEL	0.347	indeterminate
SaProt	LLR -8.69	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 11	GERP 4.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,176 bp · p 0.058 · regional, not allelic
Overall
CADD	25.2	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 0.0022% European (non-Finnish) · 26/1,179,996 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00161% 26/1,613,974 alleles · very rare

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.Phe222Ile
Coding: c.664T>A
MANE Select: NM_017654
dbSNP: rs201875833
Type: single nucleotide variant
Location: chr7:93105434 (GRCh38)
Gene constraint: LOEUF 1.773 · pLI 0.03 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 83.79 · 10 PDB
Residue 222: an α-helix

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.Phe222Leu Uncertain significance ★★ ⚠ 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
SAMD9 p.Ala123Ser 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-phe222ile (accessed [today's date]).

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