Is SAMD9L p.Asp558Val (c.1673A>T) pathogenic?

SAMD9L p.Asp558Val (c.1673A>T) is classified Uncertain significance in SAMD9L (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-10). AlphaMissense: likely pathogenic (0.5965); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SAMD9L p.Asp558Val (c.1673A>T)?

SAMD9L p.Asp558Val (c.1673A>T) is associated with Inborn genetic diseases (ClinVar).

How common is SAMD9L p.Asp558Val (c.1673A>T) in the general population?

SAMD9L p.Asp558Val (c.1673A>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SAMD9L p.Asp558Val (c.1673A>T)?

AlphaMissense predicts likely pathogenic (score 0.5965) — an in-silico prediction, not a clinical call.

SAMD9L p.Asp558Val

c.1673A>T · rs1246411637 · VCV1435007

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5965 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5965	likely pathogenic
REVEL	0.312	indeterminate
SaProt	LLR -10.39	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 1,885 bp · p 3.1e-05 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,592 alleles

Overall 0.000657% 1/152,140 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: SAMD9L
Protein: p.Asp558Val
Coding: c.1673A>T
MANE Select: NM_152703
dbSNP: rs1246411637
Type: single nucleotide variant
Location: chr7:93134299 (GRCh38)
Gene constraint: LOEUF 0.876 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.85

Full SAMD9L 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

SAMD9L p.Asp558Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
SAMD9L p.Ala1073Thr Uncertain significance ★★ ⚠ same condition
SAMD9L p.Ala1087Asp Uncertain significance ★★ ⚠ same condition
SAMD9L p.Ala1106Thr Uncertain significance ★★ ⚠ same condition
SAMD9L p.Ala1106Val Uncertain significance ★★ ⚠ same condition
SAMD9L p.Ala1109Pro Uncertain significance ★★ ⚠ same condition
SAMD9L p.Ala1156Glu Uncertain significance ★★ ⚠ same condition
SAMD9L p.Ala1156Ser 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/samd9l-p-asp558val (accessed [today's date]).

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