Is BFAR p.Pro253Arg (c.758C>G) pathogenic?

BFAR p.Pro253Arg (c.758C>G) is classified Uncertain significance in BFAR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-09). AlphaMissense: likely benign (0.3184); Ultra-rare (popmax 0.0157%, amr).

How common is BFAR p.Pro253Arg (c.758C>G) in the general population?

BFAR p.Pro253Arg (c.758C>G) is ultra-rare (popmax 0.0157%, amr) (gnomAD).

What do computational predictors say about BFAR p.Pro253Arg (c.758C>G)?

AlphaMissense predicts likely benign (score 0.3184) — an in-silico prediction, not a clinical call.

BFAR p.Pro253Arg

c.758C>G · rs142229539 · VCV3133773

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3184 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0157%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3184	likely benign
REVEL	0.467	indeterminate
SaProt	LLR -8.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
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	24.1	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 0.0157% Admixed American · 8/50,922 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00566%

Overall 0.000714% 10/1,399,828 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0157%	6,365
European (non-Finnish)	0.000174%	575,652

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.Pro253Arg
Coding: c.758C>G
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.Pro253His 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-pro253arg (accessed [today's date]).

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