Is SMARCD2 p.Ser2Ala (c.4T>G) pathogenic?

SMARCD2 p.Ser2Ala (c.4T>G) is classified Uncertain significance in SMARCD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-12). AlphaMissense: likely benign (0.0664); Very rare (popmax 0.000487%, nfe).

How common is SMARCD2 p.Ser2Ala (c.4T>G) in the general population?

SMARCD2 p.Ser2Ala (c.4T>G) is very rare (popmax 0.000487%, nfe) (gnomAD).

What do computational predictors say about SMARCD2 p.Ser2Ala (c.4T>G)?

AlphaMissense predicts likely benign (score 0.0664) — an in-silico prediction, not a clinical call.

SMARCD2 p.Ser2Ala

c.4T>G · VCV3903423

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0664 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000487%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0664	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -5.27	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 11	GERP 2, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 9,733 bp · p 8.5e-11 · regional, not allelic
Overall
CADD	22.5	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 0.000487% European (non-Finnish) · 5/1,026,920 alleles

Filtering AF 0.000143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000104%

Overall 0.000383% 5/1,306,968 alleles · very rare exomes 4/1,154,934 · genomes 1/152,034 · 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: SMARCD2
Protein: p.Ser2Ala
Coding: c.4T>G
MANE Select: NM_001098426
Type: single nucleotide variant
Location: chr17:63842671 (GRCh38)
Gene constraint: LOEUF 0.762 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.38

Full SMARCD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SMARCD2 p.Ser2Pro Uncertain significance ★★ ⚠ same residue
SMARCD2 p.Arg192Ter Pathogenic/Likely pathogenic ★★ same type
SMARCD2 c.922-3C>T Uncertain significance ★★ same type
SMARCD2 p.Ala434Thr Uncertain significance ★★ ⚠ same type
SMARCD2 p.Ala6Val Uncertain significance ★★ ⚠ same type
SMARCD2 p.Arg118Cys Uncertain significance ★★ ⚠ same type
SMARCD2 p.Arg148Gln Uncertain significance ★★ ⚠ same type
SMARCD2 p.Arg150Trp 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/smarcd2-p-ser2ala (accessed [today's date]).

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