Is ENG p.Arg199Cys (c.595C>T) pathogenic?

ENG p.Arg199Cys (c.595C>T) is classified Benign in ENG (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.201); Very rare (popmax 0.00529%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Arg199Cys (c.595C>T)?

ENG p.Arg199Cys (c.595C>T) is associated with Cardiovascular phenotype, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Arg199Cys (c.595C>T) in the general population?

ENG p.Arg199Cys (c.595C>T) is very rare (popmax 0.00529%, nfe) (gnomAD).

What do computational predictors say about ENG p.Arg199Cys (c.595C>T)?

AlphaMissense predicts likely benign (score 0.201) — an in-silico prediction, not a clinical call.

ENG p.Arg199Cys

c.595C>T · rs752195587 · VCV407127

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.201 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00529%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.201	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -10.92	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -0.38, phastCons 0.015
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	19.34	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 0.00529% European (non-Finnish) · 62/1,171,830 alleles

Filtering AF 0.00421% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00382%

Overall 0.00884% 141/1,594,262 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.116%	864
European (non-Finnish)grpmax	0.00529%	18,900
Admixed American	0.00522%	19,168
African / African-American	0.00402%	24,857
Remaining individualsnot grpmax-eligible	0.00324%	30,823
South Asian	0.00113%	88,312

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ENG
Protein: p.Arg199Cys
Coding: c.595C>T
MANE Select: NM_001114753
dbSNP: rs752195587
Type: single nucleotide variant
Location: chr9:127825789 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 199: a β-strand; a disulfide bond; the 'required for interaction with gdf2' region; the 'or2' region

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

Also linked: hereditary hemorrhagic telangiectasia

Similar variants

ENG p.Arg199Gly Uncertain significance ★ ⚠ same residue
ENG p.Arg199His Conflicting classifications of pathogenicity ★ ⚠ same residue
ENG p.Arg199Leu Uncertain significance ★ ⚠ same residue
ENG p.Arg199fs Pathogenic ★★ same residue
ENG p.Arg529His Pathogenic ★★★ ⚠ same condition
ENG p.Asn423Ser Likely pathogenic ★★★ ⚠ same condition
ENG p.Cys382Tyr Pathogenic ★★★ same condition
ENG p.Cys549Gly 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-arg199cys (accessed [today's date]).

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