Is BTNL3 p.Ser41Phe (c.122C>T) pathogenic?

BTNL3 p.Ser41Phe (c.122C>T) is classified Uncertain significance in BTNL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-08). AlphaMissense: likely benign (0.0808); Very rare (popmax 0.00132%, nfe).

How common is BTNL3 p.Ser41Phe (c.122C>T) in the general population?

BTNL3 p.Ser41Phe (c.122C>T) is very rare (popmax 0.00132%, nfe) (gnomAD).

What do computational predictors say about BTNL3 p.Ser41Phe (c.122C>T)?

AlphaMissense predicts likely benign (score 0.0808) — an in-silico prediction, not a clinical call.

BTNL3 p.Ser41Phe

c.122C>T · rs373569533 · VCV3135559

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0808 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00132%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0808	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -9.55	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 -7.4	GERP -3.7
Regional constraint	o/e 0.69	unconstrained · MANE · 17 kb · p 4.6e-11 · regional, not allelic
Overall
CADD	0.016	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 0.00132% European (non-Finnish) · 14/1,058,874 alleles

Filtering AF 0.000767% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0006%

Overall 0.000957% 14/1,463,188 alleles · very rare exomes 14/1,327,010 · genomes 0/136,178 · 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: BTNL3
Protein: p.Ser41Phe
Coding: c.122C>T
MANE Select: NM_197975
dbSNP: rs373569533
Type: single nucleotide variant
Location: chr5:180992885 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.50 · 1 PDB

Full BTNL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTNL3 p.Arg130Trp Benign/Likely benign ★★ same type
BTNL3 p.Ala267Thr Uncertain significance ★ ⚠ same type
BTNL3 p.Arg234Cys Uncertain significance ★ ⚠ same type
BTNL3 p.Arg284Gln Uncertain significance ★ ⚠ same type
BTNL3 p.Arg327Lys Uncertain significance ★ ⚠ same type
BTNL3 p.Arg359Trp Uncertain significance ★ ⚠ same type
BTNL3 p.Arg364Ser Uncertain significance ★ ⚠ same type
BTNL3 p.Arg406Gln 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/btnl3-p-ser41phe (accessed [today's date]).

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