Is CYP2C19 p.Ile331Val (c.991A>G) pathogenic?

CYP2C19 p.Ile331Val (c.991A>G) is classified Benign in CYP2C19 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-12). AlphaMissense: likely benign (0.0628); Common (popmax 98.8%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CYP2C19 p.Ile331Val (c.991A>G)?

AlphaMissense predicts likely benign (score 0.0628) — an in-silico prediction, not a clinical call.

CYP2C19 p.Ile331Val

Q: How common is CYP2C19 p.Ile331Val (c.991A>G) in the general population?

CYP2C19 p.Ile331Val (c.991A>G) is common (popmax 98.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.991A>G · rs3758581 · VCV39354

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0628 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 98.8%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.0628	likely benign
SaProt	LLR -6.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -9.7	GERP -4
Regional constraint	o/e 1.26	unconstrained · MANE · 90 kb · p 1.3e-10 · regional, not allelic
Overall
CADD	0.007	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 98.8% African / African-American · 74,097/75,032 alleles

Filtering AF 98.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 97.9%

Overall 93.9% 1,515,187/1,614,130 alleles · common exomes 1,370,162/1,461,846 · genomes 145,025/152,284 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	98.8%	1
Amishnot grpmax-eligible	97%	1
East Asian	96%	1
Admixed American	96%	1
Finnishnot grpmax-eligible	94.4%	1
Remaining individualsnot grpmax-eligible	93.9%	1
European (non-Finnish)	93.8%	1
Middle Eastern	92.8%	1
Ashkenazi Jewishnot grpmax-eligible	91.8%	1
South Asian	88.9%	1

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.Ile331Val
Coding: c.991A>G
MANE Select: NM_000769
dbSNP: rs3758581
Type: single nucleotide variant
Location: chr10:94842866 (GRCh38)
Gene constraint: LOEUF 1.668 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.24 · 1 PDB
Residue 331: a UniProt-annotated variant site (in allele cyp2c19*1b, allele cyp2c19*1c, allele cyp2c19*2a, allele cyp2c19*2b, allele cyp2c19*2c, allele cyp2c19*2e, allele cyp2c19*2f, allele cyp2c19*2g, allele cyp2c19*2h, allele cyp2c19*2j, allele cyp2c19*3a, allele cyp2c19*3b, allele cyp2c19*3c, allele cyp2c19*4a, allele cyp2c19*4b, allele cyp2c19*6, allele cyp2c19*9, allele cyp2c19*10, allele cyp2c19*11, allele cyp2c19*12, allele cyp2c19*13, allele cyp2c19*14, allele cyp2c19*15, allele cyp2c19*18, allele cyp2c19*19, allele cyp2c19*22, allele cyp2c19*23, allele cyp2c19*24, allele cyp2c19*25, allele cyp2c19*26, allele cyp2c19*27, allele cyp2c19*28, allele cyp2c19*29, allele cyp2c19*31, allele cyp2c19*32, allele cyp2c19*33 and allele cyp2c19*35)

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-ile331val (accessed [today's date]).

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