Is BFAR p.Pro253His (c.758C>A) pathogenic?

BFAR p.Pro253His (c.758C>A) is classified Uncertain significance in BFAR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). AlphaMissense: ambiguous (0.4051); Ultra-rare (popmax 0.0102%, sas).

How common is BFAR p.Pro253His (c.758C>A) in the general population?

BFAR p.Pro253His (c.758C>A) is ultra-rare (popmax 0.0102%, sas) (gnomAD).

What do computational predictors say about BFAR p.Pro253His (c.758C>A)?

AlphaMissense predicts ambiguous (score 0.4051) — an in-silico prediction, not a clinical call.

BFAR p.Pro253His

c.758C>A · rs142229539 · VCV2491908

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4051 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, sas)

Computational evidence

Protein change
AlphaMissense	0.4051	ambiguous
REVEL	0.42	indeterminate
SaProt	LLR -9.77	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 23 kb · p 0.11 · regional, not allelic
Overall
CADD	26.0	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 0.0102% South Asian · 8/78,562 alleles

Filtering AF 0.00507% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00365%

Overall 0.000571% 8/1,399,828 alleles · ultra-rare

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: BFAR
Protein: p.Pro253His
Coding: c.758C>A
MANE Select: NM_016561
dbSNP: rs142229539
Type: single nucleotide variant
Location: chr16:14655185 (GRCh38)
Gene constraint: LOEUF 1.159 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.40

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

Similar variants

BFAR p.Pro253Arg Uncertain significance ★ ⚠ same residue
BFAR p.Pro253Leu Uncertain significance ★ ⚠ same residue
BFAR p.Arg245His Benign ★★ ⚠ same type
BFAR p.Ala156Val Uncertain significance ★ ⚠ same type
BFAR p.Ala238Thr Uncertain significance ★ ⚠ same type
BFAR p.Ala238Val Uncertain significance ★ ⚠ same type
BFAR p.Ala59Val Uncertain significance ★ ⚠ same type
BFAR p.Ala90Val 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/bfar-p-pro253his (accessed [today's date]).

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