Is SMYD2 p.Pro232Arg (c.695C>G) pathogenic?

SMYD2 p.Pro232Arg (c.695C>G) is classified Uncertain significance in SMYD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-15). AlphaMissense: likely benign (0.1346); Ultra-rare (popmax 0.0165%, mid).

How common is SMYD2 p.Pro232Arg (c.695C>G) in the general population?

SMYD2 p.Pro232Arg (c.695C>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about SMYD2 p.Pro232Arg (c.695C>G)?

AlphaMissense predicts likely benign (score 0.1346) — an in-silico prediction, not a clinical call.

SMYD2 p.Pro232Arg

c.695C>G · rs140909791 · VCV2467903

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1346 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1346	likely benign
REVEL	0.567	indeterminate
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 1.9, phastCons 0.98
Regional constraint	o/e 0.91	unconstrained · MANE · 56 kb · p 0.03 · regional, not allelic
Overall
CADD	21.1	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00814% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.000805% 13/1,614,072 alleles · ultra-rare exomes 7/1,461,834 · genomes 6/152,238 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.0147%	6,820
Admixed American	0.00167%	60,020

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: SMYD2
Protein: p.Pro232Arg
Coding: c.695C>G
MANE Select: NM_020197
dbSNP: rs140909791
Type: single nucleotide variant
Location: chr1:214327714 (GRCh38)
Gene constraint: LOEUF 1.097 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.40 · 25 PDB
Residue 232: the set domain

Full SMYD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SMYD2 p.Ala197Val Uncertain significance ★ ⚠ same type
SMYD2 p.Arg253Trp Uncertain significance ★ ⚠ same type
SMYD2 p.Arg292Gln Uncertain significance ★ ⚠ same type
SMYD2 p.Arg2Gly Uncertain significance ★ ⚠ same type
SMYD2 p.Arg306Trp Uncertain significance ★ ⚠ same type
SMYD2 p.Arg48Trp Uncertain significance ★ ⚠ same type
SMYD2 p.Asn212Ser Uncertain significance ★ ⚠ same type
SMYD2 p.Asn300Asp 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/smyd2-p-pro232arg (accessed [today's date]).

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