Is EPN1 p.Ala145Val (c.434C>T) pathogenic?

EPN1 p.Ala145Val (c.434C>T) is classified Uncertain significance in EPN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-19). AlphaMissense: likely benign (0.1075); Ultra-rare (popmax 0.0204%, amr).

How common is EPN1 p.Ala145Val (c.434C>T) in the general population?

EPN1 p.Ala145Val (c.434C>T) is ultra-rare (popmax 0.0204%, amr) (gnomAD).

What do computational predictors say about EPN1 p.Ala145Val (c.434C>T)?

AlphaMissense predicts likely benign (score 0.1075) — an in-silico prediction, not a clinical call.

EPN1 p.Ala145Val

c.434C>T · rs755511778 · VCV3089761

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1075 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0204%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1075	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -8.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 2, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 6,981 bp · p 1.5e-08 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0204% Admixed American · 12/58,854 alleles

Filtering AF 0.0117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00914%

Overall 0.00224% 36/1,604,450 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0204%	4,905
South Asian	0.00335%	29,856
Remaining individualsnot grpmax-eligible	0.00322%	31,069
East Asian	0.00225%	44,372
European (non-Finnish)	0.00153%	65,349

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: EPN1
Protein: p.Ala145Val
Coding: c.434C>T
MANE Select: NM_001130072
dbSNP: rs755511778
Type: single nucleotide variant
Location: chr19:55685601 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.87 · 2 PDB

Full EPN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPN1 c.-101-1336T>C Uncertain significance ★ same type
EPN1 c.-101-1337C>A Uncertain significance ★ same type
EPN1 c.-101-1340T>C Uncertain significance ★ same type
EPN1 c.-101-1351G>T Uncertain significance ★ same type
EPN1 c.-101-813C>T Uncertain significance ★ same type
EPN1 c.-101-834C>T Uncertain significance ★ same type
EPN1 c.-101-838G>C Uncertain significance ★ same type
EPN1 c.-101-846C>T 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/epn1-p-ala145val (accessed [today's date]).

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