Is PDSS2 p.Pro93Ser (c.277C>T) pathogenic?

PDSS2 p.Pro93Ser (c.277C>T) is classified Uncertain significance in PDSS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-11). AlphaMissense: likely pathogenic (0.7379); Ultra-rare (popmax 0.0693%, afr); Associated with coenzyme Q10 deficiency, primary, 3.

What condition is associated with PDSS2 p.Pro93Ser (c.277C>T)?

PDSS2 p.Pro93Ser (c.277C>T) is associated with coenzyme Q10 deficiency, primary, 3 (ClinVar).

How common is PDSS2 p.Pro93Ser (c.277C>T) in the general population?

PDSS2 p.Pro93Ser (c.277C>T) is ultra-rare (popmax 0.0693%, afr) (gnomAD).

What do computational predictors say about PDSS2 p.Pro93Ser (c.277C>T)?

AlphaMissense predicts likely pathogenic (score 0.7379) — an in-silico prediction, not a clinical call.

PDSS2 p.Pro93Ser

c.277C>T · rs143121266 · VCV1508923

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7379 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0693%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

coenzyme Q10 deficiency, primary, 3

Computational evidence

Protein change
AlphaMissense	0.7379	likely pathogenic
REVEL	0.494	indeterminate
SaProt	LLR -11.98	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 305 kb · p 0.17 · regional, not allelic
Overall
CADD	30.0	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 0.0693% African / African-American · 52/75,054 alleles

Filtering AF 0.0542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0489%

Overall 0.00452% 73/1,614,160 alleles · ultra-rare exomes 44/1,461,820 · genomes 29/152,340 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0693%	1,443
Admixed American	0.0133%	7,504
Remaining individualsnot grpmax-eligible	0.0112%	8,930
European (non-Finnish)	0.000508%	196,670

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.Pro93Ser
Coding: c.277C>T
MANE Select: NM_020381
dbSNP: rs143121266
Type: single nucleotide variant
Location: chr6:107459009 (GRCh38)
Gene constraint: LOEUF 0.818 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.28

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

Disease context

coenzyme Q10 deficiency, primary, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PDSS2 p.Pro93Ala Uncertain significance ★ ⚠ same residue
PDSS2 p.Pro93Leu Uncertain significance ★ ⚠ same residue
PDSS2 p.Arg163His Uncertain significance ★★ ⚠ same condition
PDSS2 p.Arg366Cys Uncertain significance ★★ ⚠ same condition
PDSS2 p.Arg385Thr Uncertain significance ★★ ⚠ same condition
PDSS2 p.Asn167Ser Uncertain significance ★★ ⚠ same condition
PDSS2 p.Asn201Ser Uncertain significance ★★ ⚠ same condition
PDSS2 p.Asn390Ser Uncertain significance ★★ ⚠ same condition

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-pro93ser (accessed [today's date]).

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