Is SMARCA2 p.Ile1506Phe (c.4516A>T) pathogenic?

SMARCA2 p.Ile1506Phe (c.4516A>T) is classified Conflicting classifications of pathogenicity in SMARCA2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-08). AlphaMissense: ambiguous (0.36); Ultra-rare (popmax 0.0296%, nfe); Associated with intellectual disability-sparse hair-brachydactyly syndrome.

What condition is associated with SMARCA2 p.Ile1506Phe (c.4516A>T)?

SMARCA2 p.Ile1506Phe (c.4516A>T) is associated with intellectual disability-sparse hair-brachydactyly syndrome (ClinVar).

How common is SMARCA2 p.Ile1506Phe (c.4516A>T) in the general population?

SMARCA2 p.Ile1506Phe (c.4516A>T) is ultra-rare (popmax 0.0296%, nfe) (gnomAD).

What do computational predictors say about SMARCA2 p.Ile1506Phe (c.4516A>T)?

AlphaMissense predicts ambiguous (score 0.36) — an in-silico prediction, not a clinical call.

SMARCA2 p.Ile1506Phe

c.4516A>T · rs147135956 · VCV366251

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.36 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0296%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

intellectual disability-sparse hair-brachydactyly syndrome

Computational evidence

Protein change
AlphaMissense	0.36	ambiguous
REVEL	0.178	moderately benign-leaning
SaProt	LLR -5.32	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.98, phastCons 1
Regional constraint	o/e 1.28	unconstrained · MANE · 6,633 bp · p 0.002 · regional, not allelic
Overall
CADD	26.0	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 0.0296% European (non-Finnish) · 349/1,179,940 alleles

Filtering AF 0.027% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.0231% 373/1,613,954 alleles · ultra-rare exomes 348/1,461,784 · genomes 25/152,170 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0296%	3,381
Remaining individualsnot grpmax-eligible	0.0272%	3,676
African / African-American	0.00801%	12,486
Admixed American	0.00167%	60,006

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: SMARCA2
Protein: p.Ile1506Phe
Coding: c.4516A>T
MANE Select: NM_003070
dbSNP: rs147135956
Type: single nucleotide variant
Location: chr9:2186150 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 66.06 · 32 PDB
Residue 1506: the 'disordered' region; an α-helix; the bromo domain

Full SMARCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability-sparse hair-brachydactyly syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SMARCA2 p.Ala1160Gly Pathogenic ★★ same condition
SMARCA2 p.Ala1201Val Pathogenic/Likely pathogenic ★★ same condition
SMARCA2 p.Arg1105Cys Pathogenic ★★ same condition
SMARCA2 p.Arg1105His Pathogenic ★★ same condition
SMARCA2 p.Arg1105Pro Pathogenic/Likely pathogenic ★★ same condition
SMARCA2 p.Arg1159Gln Pathogenic/Likely pathogenic ★★ same condition
SMARCA2 p.Arg1159Gly Pathogenic ★★ same condition
SMARCA2 p.Arg1162Cys Pathogenic/Likely pathogenic ★★ 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/smarca2-p-ile1506phe (accessed [today's date]).

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