Is CYP2D6 p.Leu320Phe (c.958C>T) pathogenic?

CYP2D6 p.Leu320Phe (c.958C>T) is classified Uncertain significance in CYP2D6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely benign (0.1613); Very rare (popmax 0.00269%, afr).

How common is CYP2D6 p.Leu320Phe (c.958C>T) in the general population?

CYP2D6 p.Leu320Phe (c.958C>T) is very rare (popmax 0.00269%, afr) (gnomAD).

What do computational predictors say about CYP2D6 p.Leu320Phe (c.958C>T)?

AlphaMissense predicts likely benign (score 0.1613) — an in-silico prediction, not a clinical call.

CYP2D6 p.Leu320Phe

c.958C>T · VCV3270587

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1613 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00269%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1613	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -4.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.79, phastCons 1
Overall
CADD	17.94	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00269% African / African-American · 2/74,458 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00267% 43/1,611,174 alleles · very rare exomes 41/1,459,734 · genomes 2/151,440 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,230
Remaining individualsnot grpmax-eligible	0.00962%	10,396
African / African-Americangrpmax	0.00269%	37,229
European (non-Finnish)	0.00238%	42,077

Ashkenazi Jewish 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: CYP2D6
Protein: p.Leu320Phe
Coding: c.958C>T
MANE Select: NM_000106
Type: single nucleotide variant
Location: chr22:42127869 (GRCh38)
Gene constraint: LOEUF 1.706 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.55 · 14 PDB
Residue 320: an α-helix

Full CYP2D6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYP2D6 p.Ala237Ser Benign/Likely benign ★★ same type
CYP2D6 p.Arg296= Benign/Likely benign ★★ same type
CYP2D6 p.Arg296Cys Benign ★★ ⚠ same type
CYP2D6 p.Asn166Asp Likely benign ★★ same type
CYP2D6 p.Asp336= Likely benign ★★ same type
CYP2D6 p.Ser486= Benign/Likely benign ★★ same type
CYP2D6 p.Val11Met Likely benign ★★ same type
CYP2D6 p.Ala442Thr 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/cyp2d6-p-leu320phe (accessed [today's date]).

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