Is SMS p.Arg116Ter (c.346C>T) pathogenic?

SMS p.Arg116Ter (c.346C>T) is classified Likely pathogenic in SMS (ClinVar, Single submitter, 2 submitters; last evaluated 2022-11-09). Very rare (popmax 0.000112%, nfe); Associated with SMS-related disorder.

What condition is associated with SMS p.Arg116Ter (c.346C>T)?

SMS p.Arg116Ter (c.346C>T) is associated with SMS-related disorder (ClinVar).

How common is SMS p.Arg116Ter (c.346C>T) in the general population?

SMS p.Arg116Ter (c.346C>T) is very rare (popmax 0.000112%, nfe) (gnomAD).

SMS p.Arg116Ter

c.346C>T · VCV4484781

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Conditions

SMS-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 5 of 11
REVEL	0.083	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.2, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000112% European (non-Finnish) · 1/893,652 alleles

Overall 0.000891% 1/112,173 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: SMS
Protein: p.Arg116Ter
Coding: c.346C>T
MANE Select: NM_004595
Type: single nucleotide variant
Location: chrX:21977077 (GRCh38)
Structure: AlphaFold pLDDT 95.09 · 2 PDB
Residue 116: a β-strand

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

Disease context

SMS-related disorder

Similar variants

SMS p.Glu207Ala Uncertain significance ★ ⚠ same condition
SMS p.Glu37Asp Uncertain significance ★ ⚠ same condition
SMS p.Ile253Arg Uncertain significance ★ ⚠ same condition
SMS c.661-1C>T Likely pathogenic same condition
SMS p.Gly67Val Likely pathogenic same condition
SMS p.Glu340= Likely benign same condition
SMS p.Thr322= Likely benign same condition
SMS p.Tyr312= Likely benign 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/sms-p-arg116ter (accessed [today's date]).

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