Is CYP2C19 p.Ile205Ser (c.614T>G) pathogenic?

CYP2C19 p.Ile205Ser (c.614T>G) is classified Uncertain significance in CYP2C19 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-05). AlphaMissense: ambiguous (0.3522); Ultra-rare (popmax 0.02%, nfe).

How common is CYP2C19 p.Ile205Ser (c.614T>G) in the general population?

CYP2C19 p.Ile205Ser (c.614T>G) is ultra-rare (popmax 0.02%, nfe) (gnomAD).

What do computational predictors say about CYP2C19 p.Ile205Ser (c.614T>G)?

AlphaMissense predicts ambiguous (score 0.3522) — an in-silico prediction, not a clinical call.

CYP2C19 p.Ile205Ser

c.614T>G · rs747232605 · VCV2591511

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3522 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3522	ambiguous
REVEL	0.141	moderately benign-leaning
SaProt	LLR -6.02	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -5.7
Regional constraint	o/e 1.26	unconstrained · MANE · 90 kb · p 1.3e-10 · regional, not allelic
Overall
CADD	0.192	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 0.02% European (non-Finnish) · 236/1,179,872 alleles

Filtering AF 0.0179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0171%

Overall 0.0149% 241/1,613,660 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.02%	4,999
African / African-American	0.00534%	18,722
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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: CYP2C19
Protein: p.Ile205Ser
Coding: c.614T>G
MANE Select: NM_000769
dbSNP: rs747232605
Type: single nucleotide variant
Location: chr10:94780631 (GRCh38)
Gene constraint: LOEUF 1.668 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.24 · 1 PDB
Residue 205: an α-helix

Full CYP2C19 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYP2C19 p.Gly417= Benign ★★ same type
CYP2C19 p.His353= Benign/Likely benign ★★ same type
CYP2C19 p.Arg144Ser Uncertain significance ★ ⚠ same type
CYP2C19 p.Asn133Lys Uncertain significance ★ ⚠ same type
CYP2C19 p.Asn418Asp Uncertain significance ★ ⚠ same type
CYP2C19 p.Asp243Val Uncertain significance ★ ⚠ same type
CYP2C19 p.Asp408Asn Uncertain significance ★ ⚠ same type
CYP2C19 p.Asp414His 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/cyp2c19-p-ile205ser (accessed [today's date]).

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