Is BTLA p.Leu232Phe (c.694C>T) pathogenic?

BTLA p.Leu232Phe (c.694C>T) is classified Likely benign in BTLA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.065); Ultra-rare (popmax 0.0117%, amr).

How common is BTLA p.Leu232Phe (c.694C>T) in the general population?

BTLA p.Leu232Phe (c.694C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about BTLA p.Leu232Phe (c.694C>T)?

AlphaMissense predicts likely benign (score 0.065) — an in-silico prediction, not a clinical call.

BTLA p.Leu232Phe

c.694C>T · VCV4216801

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.065 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.065	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -7.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.26	acceptor gain · deltas
Pangolin	Δ0.30	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.55	GERP -1.1
Regional constraint	o/e 1.16	unconstrained · MANE · 266 bp · p 0.1 · regional, not allelic
Overall
CADD	4.03	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 0.0117% Admixed American · 7/59,968 alleles

Filtering AF 0.00544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00446% 72/1,613,810 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,567
European (non-Finnish)	0.00525%	19,032
African / African-American	0.00267%	37,454
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: BTLA
Protein: p.Leu232Phe
Coding: c.694C>T
MANE Select: NM_181780
Type: single nucleotide variant
Location: chr3:112466284 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 67.56 · 5 PDB

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

Similar variants

BTLA p.Arg114Leu Uncertain significance ★ ⚠ same type
BTLA p.Asn261Ser Uncertain significance ★ ⚠ same type
BTLA p.Asn268Tyr Uncertain significance ★ ⚠ same type
BTLA p.Asn75Ile Uncertain significance ★ ⚠ same type
BTLA p.Asp229Val Uncertain significance ★ ⚠ same type
BTLA p.Gln207Pro Uncertain significance ★ ⚠ same type
BTLA p.Glu92Asp Uncertain significance ★ ⚠ same type
BTLA p.Gly193Glu 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/btla-p-leu232phe (accessed [today's date]).

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