Is PDSS2 p.Phe3Leu (c.7T>C) pathogenic?

PDSS2 p.Phe3Leu (c.7T>C) is classified Benign in PDSS2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1293); Common (popmax 10.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with kidney disorder.

What condition is associated with PDSS2 p.Phe3Leu (c.7T>C)?

PDSS2 p.Phe3Leu (c.7T>C) is associated with kidney disorder (ClinVar).

What do computational predictors say about PDSS2 p.Phe3Leu (c.7T>C)?

AlphaMissense predicts likely benign (score 0.1293) — an in-silico prediction, not a clinical call.

PDSS2 p.Phe3Leu

Q: How common is PDSS2 p.Phe3Leu (c.7T>C) in the general population?

PDSS2 p.Phe3Leu (c.7T>C) is common (popmax 10.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.7T>C · rs3734675 · VCV138689

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1293 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.5%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

kidney disorder

Computational evidence

Protein change
AlphaMissense	0.1293	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -5.34	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 2.1	GERP 0.55, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 305 kb · p 0.17 · regional, not allelic
Overall
CADD	17.61	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.5% East Asian · 4,696/44,874 alleles

Filtering AF 10.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.1%

Overall 0.605% 9,761/1,613,980 alleles · common exomes 8,414/1,461,672 · genomes 1,347/152,308 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	10.5%	10
Finnishnot grpmax-eligible	2.32%	43
Admixed American	1.47%	68
Remaining individualsnot grpmax-eligible	1.12%	89
South Asian	0.854%	117
African / African-American	0.461%	217
Middle Eastern	0.116%	865
European (non-Finnish)	0.0734%	1,363
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,920

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: PDSS2
Protein: p.Phe3Leu
Coding: c.7T>C
MANE Select: NM_020381
dbSNP: rs3734675
Type: single nucleotide variant
Location: chr6:107459279 (GRCh38)
Gene constraint: LOEUF 0.818 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.28
Residue 3: a UniProt-annotated variant site (in)

Full PDSS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

kidney disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PDSS2 p.Glu303Gly Uncertain significance ★★ ⚠ same condition
PDSS2 p.Arg4Pro Benign ★★ same condition
PDSS2 p.Thr97Ile Uncertain significance ★ same condition
PDSS2 p.Val223Ile Conflicting classifications of pathogenicity ★ ⚠ same condition
PDSS2 p.Arg163His Uncertain significance ★★ ⚠ same type
PDSS2 p.Arg366Cys Uncertain significance ★★ ⚠ same type
PDSS2 p.Arg366His Uncertain significance ★★ ⚠ same type
PDSS2 p.Arg385Thr 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/pdss2-p-phe3leu (accessed [today's date]).

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