Is SAMD9L p.Ser340Pro (c.1018T>C) pathogenic?

SAMD9L p.Ser340Pro (c.1018T>C) is classified Uncertain significance in SAMD9L (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-14). AlphaMissense: likely pathogenic (0.6156); Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SAMD9L p.Ser340Pro (c.1018T>C)?

SAMD9L p.Ser340Pro (c.1018T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SAMD9L p.Ser340Pro (c.1018T>C) in the general population?

SAMD9L p.Ser340Pro (c.1018T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about SAMD9L p.Ser340Pro (c.1018T>C)?

AlphaMissense predicts likely pathogenic (score 0.6156) — an in-silico prediction, not a clinical call.

SAMD9L p.Ser340Pro

c.1018T>C · VCV4863989

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6156 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6156	likely pathogenic
REVEL	0.133	moderately benign-leaning
SaProt	LLR -13.10	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 921 bp · p 0.59 · regional, not allelic
Overall
CADD	19.85	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 0.00017% European (non-Finnish) · 2/1,179,674 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,622 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.Ser340Pro
Coding: c.1018T>C
MANE Select: NM_152703
Type: single nucleotide variant
Location: chr7:93134954 (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.Ser340Leu Uncertain significance ★ ⚠ 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-ser340pro (accessed [today's date]).

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