Is USB1 p.Glu77Lys (c.229G>A) pathogenic?

USB1 p.Glu77Lys (c.229G>A) is classified Uncertain significance in USB1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-19). AlphaMissense: likely benign (0.2315); Ultra-rare (popmax 0.0164%, mid); Associated with poikiloderma with neutropenia.

What condition is associated with USB1 p.Glu77Lys (c.229G>A)?

USB1 p.Glu77Lys (c.229G>A) is associated with poikiloderma with neutropenia (ClinVar).

How common is USB1 p.Glu77Lys (c.229G>A) in the general population?

USB1 p.Glu77Lys (c.229G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Poikiloderma with neutropenia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about USB1 p.Glu77Lys (c.229G>A)?

AlphaMissense predicts likely benign (score 0.2315) — an in-silico prediction, not a clinical call.

USB1 p.Glu77Lys

c.229G>A · rs1226771318 · VCV2171118

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2315 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

poikiloderma with neutropenia

Computational evidence

Protein change
AlphaMissense	0.2315	likely benign
REVEL	0.462	indeterminate
SaProt	LLR -11.88	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
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 0.95	unconstrained · MANE · 19 kb · p 0.36 · regional, not allelic
Overall
CADD	33.0	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 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00223% 36/1,613,850 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
European (non-Finnish)	0.00263%	38,065
East Asian	0.00223%	44,888
South Asian	0.0022%	45,545
African / African-American	0.00134%	74,886

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: USB1
Protein: p.Glu77Lys
Coding: c.229G>A
MANE Select: NM_024598
dbSNP: rs1226771318
Type: single nucleotide variant
Location: chr16:58002609 (GRCh38)
Gene constraint: LOEUF 1.016 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 83.91 · 5 PDB

Full USB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

poikiloderma with neutropenia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Poikiloderma with neutropenia (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

USB1 p.Glu77Asp Uncertain significance ★ ⚠ same residue
USB1 p.Glu77= Likely benign ★ same residue
USB1 c.266-1G>A Pathogenic ★★ same condition
USB1 p.His208Arg Likely pathogenic ★★ same condition
USB1 p.Arg112Gln Uncertain significance ★★ ⚠ same condition
USB1 p.Arg245His Uncertain significance ★★ ⚠ same condition
USB1 p.Arg252Cys Uncertain significance ★★ ⚠ same condition
USB1 p.Arg70Gln 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/usb1-p-glu77lys (accessed [today's date]).

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