Is SMC3 p.Val458= (c.1374A>G) pathogenic?

SMC3 p.Val458= (c.1374A>G) is classified Likely benign in SMC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-18). Very rare (popmax 0.00374%, nfe); Associated with Cornelia de Lange syndrome 3.

What condition is associated with SMC3 p.Val458= (c.1374A>G)?

SMC3 p.Val458= (c.1374A>G) is associated with Cornelia de Lange syndrome 3 (ClinVar).

How common is SMC3 p.Val458= (c.1374A>G) in the general population?

SMC3 p.Val458= (c.1374A>G) is very rare (popmax 0.00374%, nfe) (gnomAD).

SMC3 p.Val458=

c.1374A>G · VCV3669917

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00374%, nfe)

Conditions

Cornelia de Lange syndrome 3

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 -1.2	GERP -3.8
Overall
CADD	1.391	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00374% European (non-Finnish) · 44/1,175,618 alleles

Filtering AF 0.00284% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00253%

Overall 0.00292% 47/1,608,586 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00374%	26,719
East Asian	0.00223%	44,842
Admixed American	0.00167%	59,908
Remaining individualsnot grpmax-eligible	0.00161%	62,278

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.Val458=
Coding: c.1374A>G
MANE Select: NM_005445
Type: single nucleotide variant
Location: chr10:110589673 (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

Cornelia de Lange syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SMC3 p.Val458Ala Uncertain significance ★ same residue
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

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-val458 (accessed [today's date]).

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