Is SMS p.Ser326= (c.978G>A) pathogenic?

SMS p.Ser326= (c.978G>A) is classified Conflicting classifications of pathogenicity in SMS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-02). Ultra-rare (popmax 0.0946%, afr); Associated with Inborn genetic diseases.

What condition is associated with SMS p.Ser326= (c.978G>A)?

SMS p.Ser326= (c.978G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SMS p.Ser326= (c.978G>A) in the general population?

SMS p.Ser326= (c.978G>A) is ultra-rare (popmax 0.0946%, afr) (gnomAD).

SMS p.Ser326=

c.978G>A · rs150564614 · VCV193674

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0946%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.6	GERP -4.4
Overall
CADD	0.096	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0946% African / African-American · 54/57,083 alleles

Filtering AF 0.0744% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0672%

Overall 0.00566% 68/1,202,471 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0946%	1,057
East Asian	0.00889%	11,244
Admixed American	0.00437%	22,874
Remaining individualsnot grpmax-eligible	0.00423%	23,640
European (non-Finnish)	0.000787%	127,091

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.Ser326=
Coding: c.978G>A
MANE Select: NM_004595
dbSNP: rs150564614
Type: single nucleotide variant
Location: chrX:21992629 (GRCh38)
Structure: AlphaFold pLDDT 95.09 · 2 PDB
Residue 326: the pabs domain; 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

Similar variants

SMS p.Ser326Leu Uncertain significance ★ ⚠ same residue
SMS p.Ser326Trp Uncertain significance ★ ⚠ same residue
SMS p.Arg234Ter Pathogenic/Likely pathogenic ★★ same condition
SMS p.Gly56Ser Pathogenic ★★ ⚠ same condition
SMS p.Pro112Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
SMS p.Lys245Asn Uncertain significance ★★ ⚠ same condition
SMS p.Ser184Asn Uncertain significance ★★ ⚠ same condition
SMS p.Ala36Val 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-ser326 (accessed [today's date]).

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