Is IRF2BPL p.Ser2Ala (c.4T>G) pathogenic?

IRF2BPL p.Ser2Ala (c.4T>G) is classified Uncertain significance in IRF2BPL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely benign (0.1112); Ultra-rare (popmax 0.011%, afr); Associated with Inborn genetic diseases.

What condition is associated with IRF2BPL p.Ser2Ala (c.4T>G)?

IRF2BPL p.Ser2Ala (c.4T>G) is associated with Inborn genetic diseases (ClinVar).

How common is IRF2BPL p.Ser2Ala (c.4T>G) in the general population?

IRF2BPL p.Ser2Ala (c.4T>G) is ultra-rare (popmax 0.011%, afr) (gnomAD).

What do computational predictors say about IRF2BPL p.Ser2Ala (c.4T>G)?

AlphaMissense predicts likely benign (score 0.1112) — an in-silico prediction, not a clinical call.

IRF2BPL p.Ser2Ala

c.4T>G · VCV4622220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1112 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1112	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -4.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 0.18, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 2,140 bp · p 2.6e-05 · regional, not allelic
Overall
CADD	24.9	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 0.011% African / African-American · 8/72,630 alleles

Filtering AF 0.00542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00391%

Overall 0.00432% 68/1,572,572 alleles · ultra-rare exomes 58/1,420,390 · genomes 10/152,182 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.011%	9,079
South Asian	0.00918%	10,892
East Asian	0.00483%	20,707
European (non-Finnish)	0.00406%	24,630
Admixed American	0.00174%	57,508
Remaining individualsnot grpmax-eligible	0.00166%	60,360
Finnishnot grpmax-eligible	0.00163%	61,428

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.Ser2Ala
Coding: c.4T>G
MANE Select: NM_024496
Type: single nucleotide variant
Location: chr14:77027789 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.91 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.01 · 1 PDB

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.Ser2Leu Uncertain significance ★ ⚠ same residue
IRF2BPL p.Ser2= 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-ser2ala (accessed [today's date]).

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