Is CSMD1 p.Ile219= (c.657C>T) pathogenic?

CSMD1 p.Ile219= (c.657C>T) is classified Likely benign in CSMD1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-12). Ultra-rare (popmax 0.0603%, afr); Associated with CSMD1-related disorder.

What condition is associated with CSMD1 p.Ile219= (c.657C>T)?

CSMD1 p.Ile219= (c.657C>T) is associated with CSMD1-related disorder (ClinVar).

How common is CSMD1 p.Ile219= (c.657C>T) in the general population?

CSMD1 p.Ile219= (c.657C>T) is ultra-rare (popmax 0.0603%, afr) (gnomAD).

CSMD1 p.Ile219=

c.657C>T · rs377287620 · VCV3049406

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0603%, afr)

Conditions

CSMD1-related disorder

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 -0.21	GERP -3.7, phastCons 0.041
Overall
CADD	3.323	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0603% African / African-American · 45/74,572 alleles

Filtering AF 0.0463% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0414%

Overall 0.0221% 353/1,593,974 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0603%	1,657
European (non-Finnish)	0.0254%	3,938
Remaining individualsnot grpmax-eligible	0.0129%	7,724
Admixed American	0.0035%	28,567
South Asian	0.00114%	87,870

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: CSMD1
Protein: p.Ile219=
Coding: c.657C>T
MANE Select: NM_033225
dbSNP: rs377287620
Type: single nucleotide variant
Location: chr8:3998064 (GRCh38)
Gene constraint: LOEUF 0.586 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Residue 219: the cub 2 domain; a disulfide bond

Full CSMD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CSMD1-related disorder

Similar variants

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CSMD1 p.Gln308Leu Uncertain significance ★★ ⚠ same condition
CSMD1 p.Lys1718Asn Uncertain significance ★★ ⚠ same condition
CSMD1 p.Ser319Ter Pathogenic ★ same condition
CSMD1 c.10314+1G>A Uncertain significance ★ same condition
CSMD1 c.1344+31812G>A Uncertain significance ★ same condition
CSMD1 p.Ala1706Gly 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/csmd1-p-ile219 (accessed [today's date]).

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