Is PSD p.Leu464Phe (c.1390C>T) pathogenic?

PSD p.Leu464Phe (c.1390C>T) is classified Uncertain significance in PSD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: likely benign (0.2236); Ultra-rare (popmax 0.0493%, mid).

How common is PSD p.Leu464Phe (c.1390C>T) in the general population?

PSD p.Leu464Phe (c.1390C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about PSD p.Leu464Phe (c.1390C>T)?

AlphaMissense predicts likely benign (score 0.2236) — an in-silico prediction, not a clinical call.

PSD p.Leu464Phe

c.1390C>T · VCV3426681

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2236 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2236	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -9.34	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 5.8	GERP -1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 4,529 bp · p 0.00029 · regional, not allelic
Overall
CADD	20.8	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 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00715%

Overall 0.00167% 27/1,613,950 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
Admixed American	0.00333%	30,001
Remaining individualsnot grpmax-eligible	0.0032%	31,234
South Asian	0.0022%	45,543
European (non-Finnish)	0.00153%	65,554

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: PSD
Protein: p.Leu464Phe
Coding: c.1390C>T
MANE Select: NM_002779
Type: single nucleotide variant
Location: chr10:102413932 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 56.76
Residue 464: the 'disordered' region

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

Similar variants

PSD p.Gly336Ser Benign ★★ same type
PSD p.Leu659= Benign ★★ same type
PSD p.Ala1017Pro Uncertain significance ★ ⚠ same type
PSD p.Ala185Pro Uncertain significance ★ ⚠ same type
PSD p.Ala204Val Uncertain significance ★ ⚠ same type
PSD p.Ala260Val Uncertain significance ★ ⚠ same type
PSD p.Ala311Asp Uncertain significance ★ ⚠ same type
PSD p.Ala457Thr 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/psd-p-leu464phe (accessed [today's date]).

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