Is ENG p.Pro540His (c.1619C>A) pathogenic?

ENG p.Pro540His (c.1619C>A) is classified Uncertain significance in ENG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely benign (0.1659); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Pro540His (c.1619C>A)?

ENG p.Pro540His (c.1619C>A) is associated with Cardiovascular phenotype (ClinVar).

How common is ENG p.Pro540His (c.1619C>A) in the general population?

ENG p.Pro540His (c.1619C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ENG p.Pro540His (c.1619C>A)?

AlphaMissense predicts likely benign (score 0.1659) — an in-silico prediction, not a clinical call.

ENG p.Pro540His

c.1619C>A · VCV4843446

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1659 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1659	likely benign
REVEL	0.569	indeterminate
SaProt	LLR -7.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	23.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ENG
Protein: p.Pro540His
Coding: c.1619C>A
MANE Select: NM_001114753
Type: single nucleotide variant
Location: chr9:127818187 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 540: a β-strand

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ENG p.Pro540Leu Uncertain significance ★ ⚠ same residue
ENG p.Pro540= Likely benign ★ same residue
ENG c.1134+1G>T Pathogenic/Likely pathogenic ★★ same condition
ENG c.1311+2T>A Pathogenic ★★ same condition
ENG c.1428+1G>A Pathogenic/Likely pathogenic ★★ same condition
ENG c.1687-1G>A Pathogenic/Likely pathogenic ★★ same condition
ENG c.219+1G>A Pathogenic ★★ same condition
ENG c.219+2T>C Pathogenic/Likely pathogenic ★★ same condition

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/eng-p-pro540his (accessed [today's date]).

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