Is ESRP2 p.Arg520Ter (c.1558C>T) pathogenic?

ESRP2 p.Arg520Ter (c.1558C>T) is classified Likely pathogenic in ESRP2 (ClinVar, No assertion criteria, 1 submitter). Very rare (popmax 0.00144%, nfe); Associated with Cleft lip with or without cleft palate.

What condition is associated with ESRP2 p.Arg520Ter (c.1558C>T)?

ESRP2 p.Arg520Ter (c.1558C>T) is associated with Cleft lip with or without cleft palate (ClinVar).

How common is ESRP2 p.Arg520Ter (c.1558C>T) in the general population?

ESRP2 p.Arg520Ter (c.1558C>T) is very rare (popmax 0.00144%, nfe) (gnomAD).

ESRP2 p.Arg520Ter

c.1558C>T · rs142168544 · VCV834038

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Conditions

Cleft lip with or without cleft palate

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 15
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 0.87, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00144% European (non-Finnish) · 17/1,180,022 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.0013% 21/1,614,010 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00312%	32,011
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)grpmax	0.00144%	69,413
South Asian	0.0011%	91,088

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ESRP2
Protein: p.Arg520Ter
Coding: c.1558C>T
MANE Select: NM_024939
dbSNP: rs142168544
Type: single nucleotide variant
Location: chr16:68231331 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.87
Residue 520: the rrm 3 domain

Full ESRP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cleft lip with or without cleft palate — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ESRP2 p.Arg315His Likely pathogenic same condition
ESRP2 p.Arg250Gln Uncertain significance ⚠ same condition
ESRP2 p.Ser508Leu Uncertain significance ⚠ same condition
ESRP2 p.Glu547del Uncertain significance same condition
ESRP2 p.Gly122Arg Uncertain significance ★★ ⚠ same type
ESRP2 p.Gly463Glu Uncertain significance ★★ ⚠ same type
ESRP2 p.Leu681Phe Uncertain significance ★★ ⚠ same type
ESRP2 p.Ala691Thr Benign ★★ 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/esrp2-p-arg520ter (accessed [today's date]).

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