Is SMYD3 p.Pro23Ser (c.67C>T) pathogenic?

SMYD3 p.Pro23Ser (c.67C>T) is classified Uncertain significance in SMYD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). AlphaMissense: likely benign (0.0884); Ultra-rare (popmax 0.0168%, mid).

How common is SMYD3 p.Pro23Ser (c.67C>T) in the general population?

SMYD3 p.Pro23Ser (c.67C>T) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

What do computational predictors say about SMYD3 p.Pro23Ser (c.67C>T)?

AlphaMissense predicts likely benign (score 0.0884) — an in-silico prediction, not a clinical call.

SMYD3 p.Pro23Ser

c.67C>T · VCV4587230

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0884 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0884	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -7.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.17	GERP -3
Regional constraint	o/e 0.96	unconstrained · MANE · 758 kb · p 0.3 · regional, not allelic
Overall
CADD	1.152	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0168% Middle Eastern · 1/5,960 alleles

Filtering AF 0.00162% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000859%

Overall 0.00176% 27/1,533,102 alleles · ultra-rare exomes 25/1,380,872 · genomes 2/152,230 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,960
Admixed American	0.00612%	16,353
South Asian	0.00367%	27,284
Finnishnot grpmax-eligible	0.0017%	58,898
European (non-Finnish)	0.00167%	60,008

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: SMYD3
Protein: p.Pro23Ser
Coding: c.67C>T
MANE Select: NM_001167740
Type: single nucleotide variant
Location: chr1:246507151 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.36 · 34 PDB
Residue 23: the set domain

Full SMYD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SMYD3 c.813+8G>A Benign ★★ same type
SMYD3 p.Val67= Benign ★★ same type
SMYD3 p.Ala168Val Uncertain significance ★ ⚠ same type
SMYD3 p.Ala20Val Uncertain significance ★ same type
SMYD3 p.Ala389Thr Uncertain significance ★ ⚠ same type
SMYD3 p.Ala423Thr Uncertain significance ★ ⚠ same type
SMYD3 p.Arg103Gln Uncertain significance ★ ⚠ same type
SMYD3 p.Arg103Ter Uncertain significance ★ same type

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/smyd3-p-pro23ser (accessed [today's date]).

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