Is SMC3 p.Ser85= (c.255A>G) pathogenic?

SMC3 p.Ser85= (c.255A>G) is classified Conflicting classifications of pathogenicity in SMC3 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-06-01). Rare (popmax 0.827%, mid); Associated with Inborn genetic diseases.

What condition is associated with SMC3 p.Ser85= (c.255A>G)?

SMC3 p.Ser85= (c.255A>G) is associated with Inborn genetic diseases, Cornelia de Lange syndrome 3 (ClinVar).

How common is SMC3 p.Ser85= (c.255A>G) in the general population?

SMC3 p.Ser85= (c.255A>G) is rare (popmax 0.827%, mid) (gnomAD).

SMC3 p.Ser85=

c.255A>G · rs146433240 · VCV159980

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

rare (popmax 0.827%, mid)

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 -0.38	GERP -3.8, phastCons 0.001
Overall
CADD	3.666	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.827% Middle Eastern · 50/6,048 alleles

Filtering AF 0.644% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.595%

Overall 0.505% 8,137/1,610,920 alleles · rare exomes 7,638/1,458,590 · genomes 499/152,330 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.827%	121
Remaining individualsnot grpmax-eligible	0.648%	154
European (non-Finnish)	0.612%	163
Admixed American	0.465%	215
African / African-American	0.116%	862
South Asian	0.0978%	1,022
Finnishnot grpmax-eligible	0.0313%	3,196
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,914
East Asian	0.00223%	44,744

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: SMC3
Protein: p.Ser85=
Coding: c.255A>G
MANE Select: NM_005445
dbSNP: rs146433240
Type: single nucleotide variant
Location: chr10:110577477 (GRCh38)
Gene constraint: LOEUF 0.132 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 82.37 · 12 PDB

Full SMC3 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: Cornelia de Lange syndrome 3

Similar variants

SMC3 p.Gln1147Glu Pathogenic ★★ same condition
SMC3 p.Glu95Lys Likely pathogenic ★★ same condition
SMC3 p.Ile196Thr Pathogenic/Likely pathogenic ★★ same condition
SMC3 p.Met648Val Pathogenic/Likely pathogenic ★★ same condition
SMC3 p.Trp473Gly Likely pathogenic ★★ same condition
SMC3 c.430-3T>C Uncertain significance ★★ same condition
SMC3 p.Ala484Gly Uncertain significance ★★ ⚠ same condition
SMC3 p.Arg381Gln 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/smc3-p-ser85 (accessed [today's date]).

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