Is SMARCD1 p.Pro85Ser (c.253C>T) pathogenic?

SMARCD1 p.Pro85Ser (c.253C>T) is classified Uncertain significance in SMARCD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-25). AlphaMissense: likely benign (0.0559); Very rare (popmax 0.0055%, sas); Associated with Coffin-Siris syndrome 11.

What condition is associated with SMARCD1 p.Pro85Ser (c.253C>T)?

SMARCD1 p.Pro85Ser (c.253C>T) is associated with Coffin-Siris syndrome 11 (ClinVar).

How common is SMARCD1 p.Pro85Ser (c.253C>T) in the general population?

SMARCD1 p.Pro85Ser (c.253C>T) is very rare (popmax 0.0055%, sas) (gnomAD).

What do computational predictors say about SMARCD1 p.Pro85Ser (c.253C>T)?

AlphaMissense predicts likely benign (score 0.0559) — an in-silico prediction, not a clinical call.

SMARCD1 p.Pro85Ser

c.253C>T · rs771531874 · VCV2690049

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0559 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0055%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Coffin-Siris syndrome 11

Computational evidence

Protein change
AlphaMissense	0.0559	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -8.03	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.87, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 957 bp · p 0.18 · regional, not allelic
Overall
CADD	23.7	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

Grpmax group 0.0055% South Asian · 5/90,956 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.00031% 5/1,612,656 alleles · very rare exomes 5/1,460,328 · genomes 0/152,328 · 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.Pro85Ser
Coding: c.253C>T
MANE Select: NM_003076
dbSNP: rs771531874
Type: single nucleotide variant
Location: chr12:50086236 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.37 · 12 PDB
Residue 85: the 'disordered' region; the 'interaction with esr1, nr1h4, nr3c1, pgr and smarca4' 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.Ala487Gly Uncertain significance ★ ⚠ same condition
SMARCD1 p.Arg119Ter 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-pro85ser (accessed [today's date]).

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