Is SMG9 p.Pro44Ser (c.130C>T) pathogenic?

SMG9 p.Pro44Ser (c.130C>T) is classified Uncertain significance in SMG9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely benign (0.1); Very rare (popmax 0.000593%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SMG9 p.Pro44Ser (c.130C>T)?

SMG9 p.Pro44Ser (c.130C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SMG9 p.Pro44Ser (c.130C>T) in the general population?

SMG9 p.Pro44Ser (c.130C>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about SMG9 p.Pro44Ser (c.130C>T)?

AlphaMissense predicts likely benign (score 0.1) — an in-silico prediction, not a clinical call.

SMG9 p.Pro44Ser

c.130C>T · VCV4170594

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1	likely benign
REVEL	0.148	moderately benign-leaning
SaProt	LLR -8.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 19 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000593% European (non-Finnish) · 7/1,179,696 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,128 alleles · very rare exomes 6/1,461,046 · genomes 1/152,082 · joint denominator

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: SMG9
Protein: p.Pro44Ser
Coding: c.130C>T
MANE Select: NM_019108
Type: single nucleotide variant
Location: chr19:43750612 (GRCh38)
Gene constraint: LOEUF 1.05 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.75 · 9 PDB
Residue 44: the 'disordered' region

Full SMG9 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

SMG9 p.Gly356Val Uncertain significance ★★ ⚠ same condition
SMG9 p.Ile66Val Uncertain significance ★★ ⚠ same condition
SMG9 p.Pro415Leu Uncertain significance ★★ ⚠ same condition
SMG9 p.Val220Ile Uncertain significance ★★ ⚠ same condition
SMG9 p.Glu263Ter Pathogenic ★ same condition
SMG9 c.1340-5T>C Uncertain significance ★ same condition
SMG9 p.Ala128Thr Uncertain significance ★ ⚠ same condition
SMG9 p.Ala129Val 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/smg9-p-pro44ser (accessed [today's date]).

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