Is CYP2C19 p.Ile112Thr (c.335T>C) pathogenic?

CYP2C19 p.Ile112Thr (c.335T>C) is classified Uncertain significance in CYP2C19 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-22). AlphaMissense: likely pathogenic (0.6243); Very rare (popmax 0.004%, afr).

How common is CYP2C19 p.Ile112Thr (c.335T>C) in the general population?

CYP2C19 p.Ile112Thr (c.335T>C) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about CYP2C19 p.Ile112Thr (c.335T>C)?

AlphaMissense predicts likely pathogenic (score 0.6243) — an in-silico prediction, not a clinical call.

CYP2C19 p.Ile112Thr

c.335T>C · VCV3837857

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6243 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6243	likely pathogenic
REVEL	0.528	indeterminate
SaProt	LLR -10.97	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 5.6, phastCons 0.99
Regional constraint	o/e 1.26	unconstrained · MANE · 90 kb · p 1.3e-10 · regional, not allelic
Overall
CADD	19.92	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.004% African / African-American · 3/74,932 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,870 alleles · very rare

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.Ile112Thr
Coding: c.335T>C
MANE Select: NM_000769
Type: single nucleotide variant
Location: chr10:94775393 (GRCh38)
Gene constraint: LOEUF 1.668 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.24 · 1 PDB

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-ile112thr (accessed [today's date]).

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