Is SMS p.Ser38= (c.114G>A) pathogenic?

SMS p.Ser38= (c.114G>A) is classified Likely benign in SMS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-12-16). Ultra-rare (popmax 0.0177%, afr); Associated with syndromic X-linked intellectual disability Snyder type.

What condition is associated with SMS p.Ser38= (c.114G>A)?

SMS p.Ser38= (c.114G>A) is associated with syndromic X-linked intellectual disability Snyder type (ClinVar).

How common is SMS p.Ser38= (c.114G>A) in the general population?

SMS p.Ser38= (c.114G>A) is ultra-rare (popmax 0.0177%, afr) (gnomAD).

How is X-linked intellectual disability, Snyder type inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SMS p.Ser38=

c.114G>A · rs138924455 · VCV589182

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0177%, afr)

Conditions

syndromic X-linked intellectual disability Snyder type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.003	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -4.4
Overall
CADD	3.503	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0177% African / African-American · 10/56,381 alleles

Filtering AF 0.0131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0123%

Overall 0.0131% 158/1,206,228 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0189%	5,278
African / African-Americangrpmax	0.0177%	5,638
European (non-Finnish)	0.0152%	6,571
Admixed American	0.00441%	22,651
South Asian	0.00177%	56,650

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser38=
Coding: c.114G>A
MANE Select: NM_004595
dbSNP: rs138924455
Type: single nucleotide variant
Location: chrX:21967260 (GRCh38)
Structure: AlphaFold pLDDT 95.09 · 2 PDB
Residue 38: a β-strand

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

Disease context

syndromic X-linked intellectual disability Snyder type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked intellectual disability, Snyder type (Orphanet):

Inheritance: X-linked recessive
Onset: Adolescent, Childhood, Infancy

Similar variants

SMS p.Ser38Leu Uncertain significance ★ ⚠ 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 p.Pro112Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
SMS c.1061+2T>C Uncertain significance ★★ same condition
SMS p.Gly333Arg 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-ser38 (accessed [today's date]).

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