Is SMS p.Pro112Leu (c.335C>T) pathogenic?

SMS p.Pro112Leu (c.335C>T) is classified Pathogenic/Likely pathogenic in SMS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-04). AlphaMissense: likely benign (0.2953); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SMS p.Pro112Leu (c.335C>T)?

SMS p.Pro112Leu (c.335C>T) is associated with Inborn genetic diseases, syndromic X-linked intellectual disability Snyder type (ClinVar).

How common is SMS p.Pro112Leu (c.335C>T) in the general population?

SMS p.Pro112Leu (c.335C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SMS p.Pro112Leu (c.335C>T)?

AlphaMissense predicts likely benign (score 0.2953) — an in-silico prediction, not a clinical call.

SMS p.Pro112Leu

c.335C>T · rs2147517480 · VCV1175812

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2953 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2953	likely benign ⚠ discordant with ClinVar
REVEL	0.787	moderately pathogenic-leaning
SaProt	LLR -4.04	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.34	constrained · MANE · 22 kb · p 3.7e-21 · regional, not allelic
Overall
CADD	26.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SMS
Protein: p.Pro112Leu
Coding: c.335C>T
MANE Select: NM_004595
dbSNP: rs2147517480
Type: single nucleotide variant
Location: chrX:21977066 (GRCh38)
Structure: AlphaFold pLDDT 95.09 · 2 PDB
Residue 112: an α-helix

Full SMS 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

Also linked: syndromic X-linked intellectual disability Snyder type

Similar variants

SMS p.Pro112Gln Likely pathogenic ★ ⚠ same residue
SMS p.Arg234Ter Pathogenic/Likely pathogenic ★★ same condition
SMS p.Gly203Asp Pathogenic ★★ same condition
SMS p.Gly56Ser Pathogenic ★★ ⚠ same condition
SMS p.Ile196Thr Likely pathogenic ★★ same condition
SMS c.1061+2T>C Uncertain significance ★★ same condition
SMS p.Gly333Arg Uncertain significance ★★ ⚠ same condition
SMS p.Gly78Ala 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/sms-p-pro112leu (accessed [today's date]).

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