Is BTC p.Val138Phe (c.412G>T) pathogenic?

BTC p.Val138Phe (c.412G>T) is classified Uncertain significance in BTC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-06). AlphaMissense: likely benign (0.1239); Rare (popmax 0.123%, afr).

How common is BTC p.Val138Phe (c.412G>T) in the general population?

BTC p.Val138Phe (c.412G>T) is rare (popmax 0.123%, afr) (gnomAD).

What do computational predictors say about BTC p.Val138Phe (c.412G>T)?

AlphaMissense predicts likely benign (score 0.1239) — an in-silico prediction, not a clinical call.

BTC p.Val138Phe

c.412G>T · rs148442541 · VCV3135466

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1239 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.123%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1239	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -7.27	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 0.007	GERP -1.1, phastCons 0.001
Regional constraint	o/e 1.10	unconstrained · MANE · 46 kb · p 0.13 · regional, not allelic
Overall
CADD	19.36	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 0.123% African / African-American · 92/74,970 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0949%

Overall 0.00608% 98/1,613,066 alleles · rare exomes 47/1,460,750 · genomes 51/152,316 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.123%	815
Remaining individualsnot grpmax-eligible	0.00801%	12,491
Admixed American	0.00167%	59,826

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: BTC
Protein: p.Val138Phe
Coding: c.412G>T
MANE Select: NM_001729
dbSNP: rs148442541
Type: single nucleotide variant
Location: chr4:74750589 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.51 · 4 PDB

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

Similar variants

BTC p.Leu44Phe Benign ★★ same type
BTC p.Ala5Val Uncertain significance ★ ⚠ same type
BTC p.Arg106Lys Uncertain significance ★ ⚠ same type
BTC p.Arg146Trp Uncertain significance ★ ⚠ same type
BTC p.Arg148Cys Uncertain significance ★ ⚠ same type
BTC p.Arg37Ile Uncertain significance ★ ⚠ same type
BTC p.Arg6Gly Uncertain significance ★ ⚠ same type
BTC p.Arg6Trp 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/btc-p-val138phe (accessed [today's date]).

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