Is BTC p.Val85Met (c.253G>A) pathogenic?

BTC p.Val85Met (c.253G>A) is classified Uncertain significance in BTC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-05). AlphaMissense: ambiguous (0.3432); Very rare (popmax 0.00878%, sas).

How common is BTC p.Val85Met (c.253G>A) in the general population?

BTC p.Val85Met (c.253G>A) is very rare (popmax 0.00878%, sas) (gnomAD).

What do computational predictors say about BTC p.Val85Met (c.253G>A)?

AlphaMissense predicts ambiguous (score 0.3432) — an in-silico prediction, not a clinical call.

BTC p.Val85Met

c.253G>A · VCV3482842

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3432 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3432	ambiguous
REVEL	0.197	benign-leaning
SaProt	LLR -6.68	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.24	GERP 0.91, phastCons 0.013
Regional constraint	o/e 1.10	unconstrained · MANE · 46 kb · p 0.13 · regional, not allelic
Overall
CADD	24.2	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 0.00878% South Asian · 8/91,080 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00304% 49/1,614,122 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,385
Admixed American	0.005%	20,004
African / African-American	0.004%	25,005
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
European (non-Finnish)	0.00271%	36,875
East Asian	0.00223%	44,878
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Val85Met
Coding: c.253G>A
MANE Select: NM_001729
Type: single nucleotide variant
Location: chr4:74755887 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.51 · 4 PDB
Residue 85: a disulfide bond; a β-strand; the egf-like domain

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-val85met (accessed [today's date]).

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