Is CSMD2 p.Ala487Thr (c.1459G>A) pathogenic?

CSMD2 p.Ala487Thr (c.1459G>A) is classified Uncertain significance in CSMD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-24). AlphaMissense: likely benign (0.0588); Very rare (popmax 0.00549%, sas).

How common is CSMD2 p.Ala487Thr (c.1459G>A) in the general population?

CSMD2 p.Ala487Thr (c.1459G>A) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about CSMD2 p.Ala487Thr (c.1459G>A)?

AlphaMissense predicts likely benign (score 0.0588) — an in-silico prediction, not a clinical call.

CSMD2 p.Ala487Thr

c.1459G>A · VCV3497711

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0588 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0588	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 331 kb · p 5.5e-29 · regional, not allelic
Overall
CADD	22.4	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 is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A447T vs ClinVar A487T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% South Asian · 5/91,050 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00211% 34/1,612,626 alleles · very rare exomes 29/1,460,512 · genomes 5/152,114 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,210
African / African-American	0.00534%	18,716
Admixed American	0.00333%	29,999
Remaining individualsnot grpmax-eligible	0.0032%	31,221
European (non-Finnish)	0.0017%	58,940
Finnishnot grpmax-eligible	0.00156%	64,016

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: CSMD2
Protein: p.Ala487Thr
Coding: c.1459G>A
MANE Select: NM_001281956
Type: single nucleotide variant
Location: chr1:33792514 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 (gnomAD)

Full CSMD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSMD2 p.Pro1506= Likely benign ★★ same type
CSMD2 p.Ser3015= Benign ★★ same type
CSMD2 c.404+2T>A Uncertain significance ★ same type
CSMD2 c.6344-398G>T Uncertain significance ★ same type
CSMD2 c.6344-422A>G Uncertain significance ★ same type
CSMD2 c.6344-423T>C Uncertain significance ★ same type
CSMD2 c.6344-429G>A Uncertain significance ★ same type
CSMD2 c.6344-435G>A 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/csmd2-p-ala487thr (accessed [today's date]).

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