Is BTN3A2 p.Ser219Pro (c.655T>C) pathogenic?

BTN3A2 p.Ser219Pro (c.655T>C) is classified Uncertain significance in BTN3A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: ambiguous (0.4669); Very rare (popmax 8.47e-05%, nfe).

How common is BTN3A2 p.Ser219Pro (c.655T>C) in the general population?

BTN3A2 p.Ser219Pro (c.655T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about BTN3A2 p.Ser219Pro (c.655T>C)?

AlphaMissense predicts ambiguous (score 0.4669) — an in-silico prediction, not a clinical call.

BTN3A2 p.Ser219Pro

c.655T>C · VCV3993601

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4669	ambiguous
REVEL	0.083	moderately benign-leaning
SaProt	LLR -15.65	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.5	GERP -0.068
Regional constraint	o/e 0.88	unconstrained · MANE · 4,036 bp · p 0.061 · regional, not allelic
Overall
CADD	23.1	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 8.47e-05% European (non-Finnish) · 1/1,180,030 alleles

Overall 6.84e-05% 1/1,461,876 alleles · very rare

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: BTN3A2
Protein: p.Ser219Pro
Coding: c.655T>C
MANE Select: NM_007047
Type: single nucleotide variant
Location: chr6:26370543 (GRCh38)
Gene constraint: LOEUF 1.043 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.23 · 18 PDB
Residue 219: a disulfide bond; a β-strand

Full BTN3A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTN3A2 p.Ala110Thr Uncertain significance ★ ⚠ same type
BTN3A2 p.Ala182Asp Uncertain significance ★ ⚠ same type
BTN3A2 p.Ala192Val Uncertain significance ★ ⚠ same type
BTN3A2 p.Ala233Gly Uncertain significance ★ ⚠ same type
BTN3A2 p.Ala245Thr Uncertain significance ★ ⚠ same type
BTN3A2 p.Ala264Thr Uncertain significance ★ ⚠ same type
BTN3A2 p.Ala266Val Uncertain significance ★ ⚠ same type
BTN3A2 p.Ala48Thr 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/btn3a2-p-ser219pro (accessed [today's date]).

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