Is PSD p.Leu659= (c.1975C>T) pathogenic?

PSD p.Leu659= (c.1975C>T) is classified Benign in PSD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-21). Common (popmax 7.14%, afr) — too common for a highly-penetrant pathogenic allele.

PSD p.Leu659=

Q: How common is PSD p.Leu659= (c.1975C>T) in the general population?

PSD p.Leu659= (c.1975C>T) is common (popmax 7.14%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1975C>T · rs12254663 · VCV786174

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 7.14%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.1, phastCons 1
Overall
CADD	14.61	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.14% African / African-American · 5,354/74,970 alleles

Filtering AF 6.98% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.92%

Overall 0.385% 6,212/1,612,274 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.14%	14
Middle Eastern	0.528%	189
Ashkenazi Jewishnot grpmax-eligible	0.518%	193
Remaining individualsnot grpmax-eligible	0.516%	194
Admixed American	0.38%	263
South Asian	0.0143%	7,001
European (non-Finnish)	0.00933%	10,715

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.Leu659=
Coding: c.1975C>T
MANE Select: NM_002779
dbSNP: rs12254663
Type: single nucleotide variant
Location: chr10:102411084 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 56.76
Residue 659: the sec7 domain

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

Similar variants

PSD p.Gly336Ser 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
PSD p.Ala459Thr 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-leu659 (accessed [today's date]).

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