Is PDSS2 p.His92Pro (c.275A>C) pathogenic?

PDSS2 p.His92Pro (c.275A>C) is classified Conflicting classifications of pathogenicity in PDSS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-08). AlphaMissense: likely pathogenic (0.62); Ultra-rare (popmax 0.0102%, nfe); Associated with coenzyme Q10 deficiency, primary, 3.

What condition is associated with PDSS2 p.His92Pro (c.275A>C)?

PDSS2 p.His92Pro (c.275A>C) is associated with coenzyme Q10 deficiency, primary, 3 (ClinVar).

How common is PDSS2 p.His92Pro (c.275A>C) in the general population?

PDSS2 p.His92Pro (c.275A>C) is ultra-rare (popmax 0.0102%, nfe) (gnomAD).

What do computational predictors say about PDSS2 p.His92Pro (c.275A>C)?

AlphaMissense predicts likely pathogenic (score 0.62) — an in-silico prediction, not a clinical call.

PDSS2 p.His92Pro

c.275A>C · rs143549737 · VCV214991

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.62 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

coenzyme Q10 deficiency, primary, 3

Computational evidence

Protein change
AlphaMissense	0.62	likely pathogenic
REVEL	0.635	indeterminate
SaProt	LLR -12.48	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 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 305 kb · p 0.17 · regional, not allelic
Overall
CADD	33.0	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 0.0102% European (non-Finnish) · 120/1,179,956 alleles

Filtering AF 0.00867% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.00762% 123/1,613,720 alleles · ultra-rare exomes 112/1,461,794 · genomes 11/151,926 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0102%	9,833
African / African-American	0.00267%	37,403
South Asian	0.0011%	91,066

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.His92Pro
Coding: c.275A>C
MANE Select: NM_020381
dbSNP: rs143549737
Type: single nucleotide variant
Location: chr6:107459011 (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.His92= Likely benign ★ 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
PDSS2 p.Asp180His 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-his92pro (accessed [today's date]).

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