Is EVC p.His217Arg (c.650A>G) pathogenic?

EVC p.His217Arg (c.650A>G) is classified Uncertain significance in EVC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-07). AlphaMissense: ambiguous (0.5296); Ultra-rare (popmax 0.0111%, eas); Associated with Inborn genetic diseases.

What condition is associated with EVC p.His217Arg (c.650A>G)?

EVC p.His217Arg (c.650A>G) is associated with Inborn genetic diseases (ClinVar).

How common is EVC p.His217Arg (c.650A>G) in the general population?

EVC p.His217Arg (c.650A>G) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about EVC p.His217Arg (c.650A>G)?

AlphaMissense predicts ambiguous (score 0.5296) — an in-silico prediction, not a clinical call.

EVC p.His217Arg

c.650A>G · VCV3276652

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5296 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5296	ambiguous · top 9% in EVC
REVEL	0.3	indeterminate
SaProt	LLR -8.74	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	19.54	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 0.0111% East Asian · 5/44,878 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000743% 12/1,614,106 alleles · ultra-rare exomes 10/1,461,796 · genomes 2/152,310 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,976
European (non-Finnish)	0.000593%	168,569

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.His217Arg
Coding: c.650A>G
MANE Select: NM_153717
Type: single nucleotide variant
Location: chr4:5733383 (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.His217= Likely benign ★ 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-his217arg (accessed [today's date]).

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