Is ESPNL p.Asp149Glu (c.447C>A) pathogenic?

ESPNL p.Asp149Glu (c.447C>A) is classified Uncertain significance in ESPNL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-27). AlphaMissense: ambiguous (0.5368); Very rare (popmax 8.62e-05%, nfe).

How common is ESPNL p.Asp149Glu (c.447C>A) in the general population?

ESPNL p.Asp149Glu (c.447C>A) is very rare (popmax 8.62e-05%, nfe) (gnomAD).

What do computational predictors say about ESPNL p.Asp149Glu (c.447C>A)?

AlphaMissense predicts ambiguous (score 0.5368) — an in-silico prediction, not a clinical call.

ESPNL p.Asp149Glu

c.447C>A · rs1691498720 · VCV2314082

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5368 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.62e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5368	ambiguous
REVEL	0.279	benign-leaning
SaProt	LLR -10.43	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -1.8, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.0064 · regional, not allelic
Overall
CADD	23.2	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 8.62e-05% European (non-Finnish) · 1/1,159,652 alleles

Overall 7.05e-05% 1/1,418,288 alleles · very rare

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.Asp149Glu
Coding: c.447C>A
MANE Select: NM_194312
dbSNP: rs1691498720
Type: single nucleotide variant
Location: chr2:238102093 (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-asp149glu (accessed [today's date]).

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