Is FASTKD2 p.Ser504Pro (c.1510T>C) pathogenic?

FASTKD2 p.Ser504Pro (c.1510T>C) is classified Uncertain significance in FASTKD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-01). AlphaMissense: likely pathogenic (0.8652); Absent from gnomAD v4.1; Associated with combined oxidative phosphorylation deficiency 44.

What condition is associated with FASTKD2 p.Ser504Pro (c.1510T>C)?

FASTKD2 p.Ser504Pro (c.1510T>C) is associated with combined oxidative phosphorylation deficiency 44 (ClinVar).

How common is FASTKD2 p.Ser504Pro (c.1510T>C) in the general population?

FASTKD2 p.Ser504Pro (c.1510T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FASTKD2 p.Ser504Pro (c.1510T>C)?

AlphaMissense predicts likely pathogenic (score 0.8652) — an in-silico prediction, not a clinical call.

FASTKD2 p.Ser504Pro

c.1510T>C · VCV3585349

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8652 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

combined oxidative phosphorylation deficiency 44

Computational evidence

Protein change
AlphaMissense	0.8652	likely pathogenic · top 4% in FASTKD2
REVEL	0.483	indeterminate
SaProt	LLR -11.74	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 2.9	GERP 1.4, phastCons 0.98
Regional constraint	o/e 0.95	unconstrained · MANE · 25 kb · p 0.12 · regional, not allelic
Overall
CADD	24.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FASTKD2
Protein: p.Ser504Pro
Coding: c.1510T>C
MANE Select: NM_001136193
Type: single nucleotide variant
Location: chr2:206786815 (GRCh38)
Gene constraint: LOEUF 1.203 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.39
Residue 504: a UniProt-annotated variant site (in coxpd44; decreased mitochondrial large ribosomal subunit assembly); a UniProt-annotated variant site (in coxpd44)

Full FASTKD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined oxidative phosphorylation deficiency 44 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FASTKD2 c.882-1G>A Pathogenic/Likely pathogenic ★★ same condition
FASTKD2 c.991-2A>G Likely pathogenic ★★ same condition
FASTKD2 p.Arg290Ter Pathogenic ★★ same condition
FASTKD2 p.Arg358Ter Pathogenic/Likely pathogenic ★★ same condition
FASTKD2 p.Arg432Ter Pathogenic/Likely pathogenic ★★ same condition
FASTKD2 p.Cys283Ter Pathogenic/Likely pathogenic ★★ same condition
FASTKD2 p.Gln564Ter Pathogenic/Likely pathogenic ★★ same condition
FASTKD2 p.Trp302Ter Pathogenic/Likely pathogenic ★★ 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/fastkd2-p-ser504pro (accessed [today's date]).

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