Is PDLIM3 p.Ser226= (c.678G>A) pathogenic?

PDLIM3 p.Ser226= (c.678G>A) is classified Benign/Likely benign in PDLIM3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). Common (popmax 9.97%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hypertrophic cardiomyopathy.

What condition is associated with PDLIM3 p.Ser226= (c.678G>A)?

PDLIM3 p.Ser226= (c.678G>A) is associated with hypertrophic cardiomyopathy, dilated cardiomyopathy (ClinVar).

PDLIM3 p.Ser226=

Q: How common is PDLIM3 p.Ser226= (c.678G>A) in the general population?

PDLIM3 p.Ser226= (c.678G>A) is common (popmax 9.97%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.678G>A · rs34943562 · VCV138671

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 9.97%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

hypertrophic cardiomyopathy

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 -11	GERP -5.2
Overall
CADD	0.203	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.97% African / African-American · 7,475/74,986 alleles

Filtering AF 9.78% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.7%

Overall 0.548% 8,798/1,605,846 alleles · common exomes 4,392/1,453,666 · genomes 4,406/152,180 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.97%	10
Remaining individualsnot grpmax-eligible	0.77%	130
Admixed American	0.74%	135
Middle Eastern	0.38%	263
European (non-Finnish)	0.0297%	3,371
South Asian	0.022%	4,553
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,401
East Asian	0.00223%	44,862

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: PDLIM3
Protein: p.Ser226=
Coding: c.678G>A
MANE Select: NM_014476
dbSNP: rs34943562
Type: single nucleotide variant
Location: chr4:185506637 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.98

Full PDLIM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypertrophic cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy

Similar variants

PDLIM3 p.Ser226Leu Uncertain significance ★★ ⚠ same residue
PDLIM3 p.Ser226Pro Uncertain significance ★★ ⚠ same residue
PDLIM3 p.Ala168Val Uncertain significance ★★ ⚠ same condition
PDLIM3 p.Ala171Thr Uncertain significance ★★ ⚠ same condition
PDLIM3 p.Ala304Gly Uncertain significance ★★ ⚠ same condition
PDLIM3 p.Ala308Thr Uncertain significance ★★ ⚠ same condition
PDLIM3 p.Ala308Val Uncertain significance ★★ ⚠ same condition
PDLIM3 p.Ala345Thr 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/pdlim3-p-ser226 (accessed [today's date]).

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