Is SMARCD1 p.Ala487Gly (c.1460C>G) pathogenic?

SMARCD1 p.Ala487Gly (c.1460C>G) is classified Uncertain significance in SMARCD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-31). AlphaMissense: ambiguous (0.3951); Very rare (popmax 0.00988%, sas); Associated with Coffin-Siris syndrome 11.

What condition is associated with SMARCD1 p.Ala487Gly (c.1460C>G)?

SMARCD1 p.Ala487Gly (c.1460C>G) is associated with Coffin-Siris syndrome 11 (ClinVar).

How common is SMARCD1 p.Ala487Gly (c.1460C>G) in the general population?

SMARCD1 p.Ala487Gly (c.1460C>G) is very rare (popmax 0.00988%, sas) (gnomAD).

What do computational predictors say about SMARCD1 p.Ala487Gly (c.1460C>G)?

AlphaMissense predicts ambiguous (score 0.3951) — an in-silico prediction, not a clinical call.

SMARCD1 p.Ala487Gly

c.1460C>G · rs541161761 · VCV2436141

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Coffin-Siris syndrome 11

Computational evidence

Protein change
AlphaMissense	0.3951	ambiguous
REVEL	0.242	benign-leaning
SaProt	LLR -13.32	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 13 kb · p 8.4e-25 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00988% South Asian · 9/91,074 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.000558% 9/1,614,064 alleles · very rare exomes 7/1,461,804 · genomes 2/152,260 · joint denominator

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: SMARCD1
Protein: p.Ala487Gly
Coding: c.1460C>G
MANE Select: NM_003076
dbSNP: rs541161761
Type: single nucleotide variant
Location: chr12:50098781 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.37 · 12 PDB
Residue 487: a UniProt-annotated variant site (in css11; does not affect the interaction with smarcc1 and smarca4); an α-helix; the 'necessary for gr/nr3c1-mediated remodeling and transcription from chromatin; required for gr/nr3c1 interaction with the brg1/smarca4 complex in vivo' region

Full SMARCD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Coffin-Siris syndrome 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SMARCD1 p.Thr189Ser Uncertain significance ★★ ⚠ same condition
SMARCD1 c.178-9C>T Benign ★★ same condition
SMARCD1 p.Gln112His Benign/Likely benign ★★ same condition
SMARCD1 p.Arg503Ter Pathogenic ★ same condition
SMARCD1 p.Ile424Thr Likely pathogenic ★ same condition
SMARCD1 c.1393-1G>A Uncertain significance ★ same condition
SMARCD1 p.Arg119Ter Uncertain significance ★ same condition
SMARCD1 p.Gly80Ser 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/smarcd1-p-ala487gly (accessed [today's date]).

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