Is BNIP2 p.Ile147Thr (c.440T>C) pathogenic?

BNIP2 p.Ile147Thr (c.440T>C) is classified Uncertain significance in BNIP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-16). AlphaMissense: likely pathogenic (0.8081); Very rare (popmax 0.00721%, nfe).

How common is BNIP2 p.Ile147Thr (c.440T>C) in the general population?

BNIP2 p.Ile147Thr (c.440T>C) is very rare (popmax 0.00721%, nfe) (gnomAD).

What do computational predictors say about BNIP2 p.Ile147Thr (c.440T>C)?

AlphaMissense predicts likely pathogenic (score 0.8081) — an in-silico prediction, not a clinical call.

BNIP2 p.Ile147Thr

c.440T>C · rs374260903 · VCV2402209

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8081 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00721%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8081	likely pathogenic
REVEL	0.742	pathogenic-leaning
SaProt	LLR -13.70	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.97 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 18 kb · p 0.027 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00721% European (non-Finnish) · 85/1,179,618 alleles

Filtering AF 0.00596% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.00558% 90/1,612,904 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00721%	13,878
Remaining individualsnot grpmax-eligible	0.00481%	20,804
Admixed American	0.00167%	59,750
African / African-American	0.00134%	74,866

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: BNIP2
Protein: p.Ile147Thr
Coding: c.440T>C
MANE Select: NM_004330
dbSNP: rs374260903
Type: single nucleotide variant
Location: chr15:59677943 (GRCh38)
Gene constraint: LOEUF 1.048 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.06
Residue 147: the cral-trio domain

Full BNIP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BNIP2 p.Ile147Val Uncertain significance ★ ⚠ same residue
BNIP2 c.-101C>G Uncertain significance ★ same type
BNIP2 c.-129G>A Uncertain significance ★ same type
BNIP2 c.-150C>G Uncertain significance ★ same type
BNIP2 c.-159G>A Uncertain significance ★ same type
BNIP2 c.-159G>C Uncertain significance ★ same type
BNIP2 c.-164G>A Uncertain significance ★ same type
BNIP2 c.-173C>T 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/bnip2-p-ile147thr (accessed [today's date]).

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