Is IRF2BPL p.Ser397Pro (c.1189T>C) pathogenic?

IRF2BPL p.Ser397Pro (c.1189T>C) is classified Uncertain significance in IRF2BPL (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-01). AlphaMissense: likely pathogenic (0.9589); Absent from gnomAD v4.1.

How common is IRF2BPL p.Ser397Pro (c.1189T>C) in the general population?

IRF2BPL p.Ser397Pro (c.1189T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IRF2BPL p.Ser397Pro (c.1189T>C)?

AlphaMissense predicts likely pathogenic (score 0.9589) — an in-silico prediction, not a clinical call.

IRF2BPL p.Ser397Pro

c.1189T>C · rs1885132751 · VCV932676

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9589 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9589	likely pathogenic
REVEL	0.151	moderately benign-leaning
SaProt	LLR -13.82	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP -1.2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 2,140 bp · p 2.6e-05 · regional, not allelic
Overall
CADD	26.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: IRF2BPL
Protein: p.Ser397Pro
Coding: c.1189T>C
MANE Select: NM_024496
dbSNP: rs1885132751
Type: single nucleotide variant
Location: chr14:77026604 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.91 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.01 · 1 PDB
Residue 397: 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.Ser397Trp Uncertain significance ★ ⚠ same residue
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

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-ser397pro (accessed [today's date]).

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