Is ESPNL p.Pro329Leu (c.986C>T) pathogenic?

ESPNL p.Pro329Leu (c.986C>T) is classified Uncertain significance in ESPNL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-26). AlphaMissense: likely benign (0.119); Ultra-rare (popmax 0.0155%, nfe).

How common is ESPNL p.Pro329Leu (c.986C>T) in the general population?

ESPNL p.Pro329Leu (c.986C>T) is ultra-rare (popmax 0.0155%, nfe) (gnomAD).

What do computational predictors say about ESPNL p.Pro329Leu (c.986C>T)?

AlphaMissense predicts likely benign (score 0.119) — an in-silico prediction, not a clinical call.

ESPNL p.Pro329Leu

c.986C>T · VCV3510381

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.119 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0155%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.119	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -11.96	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.032	GERP -1.3, phastCons 0.61
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.0064 · regional, not allelic
Overall
CADD	19.12	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 0.0155% European (non-Finnish) · 183/1,178,104 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.013%

Overall 0.0122% 197/1,608,550 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0155%	6,438
Remaining individualsnot grpmax-eligible	0.00642%	15,572
Admixed American	0.00505%	19,801
South Asian	0.00443%	22,587
African / African-American	0.00267%	37,501
East Asian	0.00224%	44,722

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.Pro329Leu
Coding: c.986C>T
MANE Select: NM_194312
Type: single nucleotide variant
Location: chr2:238117033 (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.Pro329Ser 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-pro329leu (accessed [today's date]).

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