Is BNIP2 p.Ser266Leu (c.797C>T) pathogenic?

BNIP2 p.Ser266Leu (c.797C>T) is classified Uncertain significance in BNIP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-02). AlphaMissense: ambiguous (0.3805); Very rare (popmax 0.00223%, eas).

How common is BNIP2 p.Ser266Leu (c.797C>T) in the general population?

BNIP2 p.Ser266Leu (c.797C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BNIP2 p.Ser266Leu (c.797C>T)?

AlphaMissense predicts ambiguous (score 0.3805) — an in-silico prediction, not a clinical call.

BNIP2 p.Ser266Leu

c.797C>T · rs756869353 · VCV2332134

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3805 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3805	ambiguous
REVEL	0.767	pathogenic-leaning
SaProt	LLR -12.84	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 18 kb · p 0.027 · regional, not allelic
Overall
CADD	33.0	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 0.00223% East Asian · 1/44,804 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00031% 5/1,611,578 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,804
African / African-American	0.00134%	74,810
European (non-Finnish)	0.000255%	392,810

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.Ser266Leu
Coding: c.797C>T
MANE Select: NM_004330
dbSNP: rs756869353
Type: single nucleotide variant
Location: chr15:59668988 (GRCh38)
Gene constraint: LOEUF 1.048 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.06
Residue 266: the cral-trio domain

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

Similar variants

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
BNIP2 c.-234G>A 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-ser266leu (accessed [today's date]).

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