Is ESPNL p.Leu603Pro (c.1808T>C) pathogenic?

ESPNL p.Leu603Pro (c.1808T>C) is classified Uncertain significance in ESPNL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-21). AlphaMissense: likely pathogenic (0.8946); Very rare (popmax 0.00742%, nfe).

How common is ESPNL p.Leu603Pro (c.1808T>C) in the general population?

ESPNL p.Leu603Pro (c.1808T>C) is very rare (popmax 0.00742%, nfe) (gnomAD).

What do computational predictors say about ESPNL p.Leu603Pro (c.1808T>C)?

AlphaMissense predicts likely pathogenic (score 0.8946) — an in-silico prediction, not a clinical call.

ESPNL p.Leu603Pro

c.1808T>C · rs148153794 · VCV2400436

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00742%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8946	likely pathogenic · top 6% in ESPNL
REVEL	0.36	indeterminate
SaProt	LLR -7.15	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -0.76, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.0064 · regional, not allelic
Overall
CADD	24.6	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 0.00742% European (non-Finnish) · 87/1,171,728 alleles

Filtering AF 0.00609% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00569%

Overall 0.00583% 93/1,596,036 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00742%	13,468
Remaining individualsnot grpmax-eligible	0.00648%	15,431
Admixed American	0.00174%	57,482
African / African-American	0.00134%	74,718

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.Leu603Pro
Coding: c.1808T>C
MANE Select: NM_194312
dbSNP: rs148153794
Type: single nucleotide variant
Location: chr2:238130522 (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.Leu603Val Uncertain significance ★ ⚠ same residue
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

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-leu603pro (accessed [today's date]).

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