Is IRF2BPL p.Pro712Ser (c.2134C>T) pathogenic?

IRF2BPL p.Pro712Ser (c.2134C>T) is classified Uncertain significance in IRF2BPL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-15). AlphaMissense: likely pathogenic (0.9464); Very rare (popmax 0.00538%, amr).

How common is IRF2BPL p.Pro712Ser (c.2134C>T) in the general population?

IRF2BPL p.Pro712Ser (c.2134C>T) is very rare (popmax 0.00538%, amr) (gnomAD).

What do computational predictors say about IRF2BPL p.Pro712Ser (c.2134C>T)?

AlphaMissense predicts likely pathogenic (score 0.9464) — an in-silico prediction, not a clinical call.

IRF2BPL p.Pro712Ser

c.2134C>T · VCV4922557

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9464 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00538%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9464	likely pathogenic
REVEL	0.451	indeterminate
SaProt	LLR -7.84	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 2,140 bp · p 2.6e-05 · regional, not allelic
Overall
CADD	26.8	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 0.00538% Admixed American · 3/55,776 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000696%

Overall 0.000383% 6/1,566,760 alleles · very rare exomes 4/1,414,512 · genomes 2/152,248 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00538%	18,592
European (non-Finnish)	0.00026%	384,530

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.Pro712Ser
Coding: c.2134C>T
MANE Select: NM_024496
Type: single nucleotide variant
Location: chr14:77025659 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.91 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.01 · 1 PDB
Residue 712: 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

Similar variants

IRF2BPL p.Arg188Ter Pathogenic/Likely pathogenic ★★ same type
IRF2BPL p.Gln117Ter Likely pathogenic ★★ same type
IRF2BPL p.Gln119Ter Likely pathogenic ★★ same type
IRF2BPL p.Gln120Ter Pathogenic/Likely pathogenic ★★ same type
IRF2BPL p.Gln121Ter Pathogenic/Likely pathogenic ★★ same type
IRF2BPL p.Gln122Ter Pathogenic/Likely pathogenic ★★ same type
IRF2BPL p.Gln167Ter Pathogenic/Likely pathogenic ★★ same type
IRF2BPL p.Gln497Ter Pathogenic/Likely pathogenic ★★ 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/irf2bpl-p-pro712ser (accessed [today's date]).

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