Is EVC p.His140Pro (c.419A>C) pathogenic?

EVC p.His140Pro (c.419A>C) is classified Uncertain significance in EVC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). AlphaMissense: likely benign (0.2386); Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EVC p.His140Pro (c.419A>C)?

EVC p.His140Pro (c.419A>C) is associated with Inborn genetic diseases (ClinVar).

How common is EVC p.His140Pro (c.419A>C) in the general population?

EVC p.His140Pro (c.419A>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about EVC p.His140Pro (c.419A>C)?

AlphaMissense predicts likely benign (score 0.2386) — an in-silico prediction, not a clinical call.

EVC p.His140Pro

c.419A>C · VCV4618907

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2386 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2386	likely benign
REVEL	0.327	indeterminate
SaProt	LLR -4.56	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	23.3	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 0.00017% European (non-Finnish) · 2/1,179,882 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,160 alleles · very rare exomes 1/1,461,324 · genomes 1/151,836 · joint denominator

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: EVC
Protein: p.His140Pro
Coding: c.419A>C
MANE Select: NM_153717
Type: single nucleotide variant
Location: chr4:5731459 (GRCh38)
Gene constraint: LOEUF 1.134 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.49

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EVC p.His140Tyr Uncertain significance ⚠ same residue
EVC p.Ala20Pro Uncertain significance ★★ ⚠ same condition
EVC p.Ala365Asp Uncertain significance ★★ ⚠ same condition
EVC p.Ala365Thr Uncertain significance ★★ ⚠ same condition
EVC p.Arg340Gln Uncertain significance ★★ ⚠ same condition
EVC p.Arg438Trp Uncertain significance ★★ ⚠ same condition
EVC p.Arg622Gln Uncertain significance ★★ ⚠ same condition
EVC p.Arg647Trp Uncertain significance ★★ ⚠ 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/evc-p-his140pro (accessed [today's date]).

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