Is SMYD2 p.Phe166Ile (c.496T>A) pathogenic?

SMYD2 p.Phe166Ile (c.496T>A) is classified Uncertain significance in SMYD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-18). AlphaMissense: likely benign (0.1559); Absent from gnomAD v4.1.

How common is SMYD2 p.Phe166Ile (c.496T>A) in the general population?

SMYD2 p.Phe166Ile (c.496T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SMYD2 p.Phe166Ile (c.496T>A)?

AlphaMissense predicts likely benign (score 0.1559) — an in-silico prediction, not a clinical call.

SMYD2 p.Phe166Ile

c.496T>A · rs2527677374 · VCV2271927

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1559 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1559	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -7.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.11	GERP 0.7, phastCons 0.016
Regional constraint	o/e 0.91	unconstrained · MANE · 56 kb · p 0.03 · regional, not allelic
Overall
CADD	14.69	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SMYD2
Protein: p.Phe166Ile
Coding: c.496T>A
MANE Select: NM_020197
dbSNP: rs2527677374
Type: single nucleotide variant
Location: chr1:214318945 (GRCh38)
Gene constraint: LOEUF 1.097 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.40 · 25 PDB
Residue 166: the set domain; an α-helix

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-phe166ile (accessed [today's date]).

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