Is ESPNL p.Arg878Cys (c.2632C>T) pathogenic?

ESPNL p.Arg878Cys (c.2632C>T) is classified Uncertain significance in ESPNL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: ambiguous (0.4139); Ultra-rare (popmax 0.075%, eas).

How common is ESPNL p.Arg878Cys (c.2632C>T) in the general population?

ESPNL p.Arg878Cys (c.2632C>T) is ultra-rare (popmax 0.075%, eas) (gnomAD).

What do computational predictors say about ESPNL p.Arg878Cys (c.2632C>T)?

AlphaMissense predicts ambiguous (score 0.4139) — an in-silico prediction, not a clinical call.

ESPNL p.Arg878Cys

c.2632C>T · VCV4251107

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4139 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.075%, eas)

Computational evidence

Protein change
AlphaMissense	0.4139	ambiguous
REVEL	0.623	indeterminate
SaProt	LLR -12.07	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.87, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.0064 · regional, not allelic
Overall
CADD	26.3	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 0.075% East Asian · 33/44,004 alleles

Filtering AF 0.0548% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0479%

Overall 0.00351% 56/1,594,850 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.075%	1,333
African / African-American	0.0201%	4,983
Remaining individualsnot grpmax-eligible	0.00649%	15,404
South Asian	0.00113%	88,740
European (non-Finnish)	0.000256%	390,497

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: ESPNL
Protein: p.Arg878Cys
Coding: c.2632C>T
MANE Select: NM_194312
Type: single nucleotide variant
Location: chr2:238131346 (GRCh38)
Gene constraint: LOEUF 1.651 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.57

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

Similar variants

ESPNL p.Arg167Gln Benign ★★ same type
ESPNL p.Arg351Cys Benign ★★ ⚠ same type
ESPNL c.672+1G>A Uncertain significance ★ same type
ESPNL p.Ala112Ser Uncertain significance ★ ⚠ same type
ESPNL p.Ala144Asp Uncertain significance ★ ⚠ same type
ESPNL p.Ala144Thr Uncertain significance ★ ⚠ same type
ESPNL p.Ala145Thr Uncertain significance ★ ⚠ same type
ESPNL p.Ala159Thr Uncertain significance ★ ⚠ 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/espnl-p-arg878cys (accessed [today's date]).

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