Is IRF2BPL p.Pro253Ser (c.757C>T) pathogenic?

IRF2BPL p.Pro253Ser (c.757C>T) is classified Likely benign in IRF2BPL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-07). AlphaMissense: ambiguous (0.5219); Ultra-rare (popmax 0.0272%, sas); Associated with Inborn genetic diseases.

What condition is associated with IRF2BPL p.Pro253Ser (c.757C>T)?

IRF2BPL p.Pro253Ser (c.757C>T) is associated with Inborn genetic diseases (ClinVar).

How common is IRF2BPL p.Pro253Ser (c.757C>T) in the general population?

IRF2BPL p.Pro253Ser (c.757C>T) is ultra-rare (popmax 0.0272%, sas) (gnomAD).

What do computational predictors say about IRF2BPL p.Pro253Ser (c.757C>T)?

AlphaMissense predicts ambiguous (score 0.5219) — an in-silico prediction, not a clinical call.

IRF2BPL p.Pro253Ser

c.757C>T · VCV3530016

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5219 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0272%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5219	ambiguous
REVEL	0.211	benign-leaning
SaProt	LLR -7.12	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 8.1	GERP 0.097, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 2,140 bp · p 2.6e-05 · regional, not allelic
Overall
CADD	21.6	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 0.0272% South Asian · 23/84,694 alleles

Filtering AF 0.0185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00169% 26/1,542,716 alleles · ultra-rare exomes 26/1,390,444 · genomes 0/152,272 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0272%	3,682
Remaining individualsnot grpmax-eligible	0.00334%	29,951
African / African-American	0.00136%	73,502

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: IRF2BPL
Protein: p.Pro253Ser
Coding: c.757C>T
MANE Select: NM_024496
Type: single nucleotide variant
Location: chr14:77027036 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.91 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.01 · 1 PDB
Residue 253: the 'disordered' region; a UniProt-annotated variant site (in nedamss); a UniProt-annotated variant site (in nedamss; loss of function)

Full IRF2BPL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IRF2BPL p.Pro253His Uncertain significance ★ ⚠ same residue
IRF2BPL p.Pro253= Likely benign same residue
IRF2BPL p.Arg188Ter Pathogenic/Likely pathogenic ★★ same condition
IRF2BPL p.Ala353Thr Uncertain significance ★★ ⚠ same condition
IRF2BPL p.Ala785Val Uncertain significance ★★ ⚠ same condition
IRF2BPL p.Arg228Pro Uncertain significance ★★ same condition
IRF2BPL p.Gly264Cys Uncertain significance ★★ ⚠ same condition
IRF2BPL p.Gly536Val Uncertain significance ★★ ⚠ same condition

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/irf2bpl-p-pro253ser (accessed [today's date]).

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