Is ESPNL p.Asp76Val (c.227A>T) pathogenic?

ESPNL p.Asp76Val (c.227A>T) is classified Uncertain significance in ESPNL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely pathogenic (0.9284); Ultra-rare (popmax 0.0467%, mid).

How common is ESPNL p.Asp76Val (c.227A>T) in the general population?

ESPNL p.Asp76Val (c.227A>T) is ultra-rare (popmax 0.0467%, mid) (gnomAD).

What do computational predictors say about ESPNL p.Asp76Val (c.227A>T)?

AlphaMissense predicts likely pathogenic (score 0.9284) — an in-silico prediction, not a clinical call.

ESPNL p.Asp76Val

c.227A>T · VCV4251118

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9284 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0467%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9284	likely pathogenic · top 4% in ESPNL
REVEL	0.347	indeterminate
SaProt	LLR -12.33	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.8	GERP 1.7, 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

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0467% Middle Eastern · 2/4,280 alleles

Filtering AF 0.00825% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.00117% 17/1,449,844 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0467%	2,140
Remaining individualsnot grpmax-eligible	0.00359%	27,880
European (non-Finnish)	0.00117%	85,251

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.Asp76Val
Coding: c.227A>T
MANE Select: NM_194312
Type: single nucleotide variant
Location: chr2:238100646 (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-asp76val (accessed [today's date]).

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