Is PTCD3 p.Pro640Ala (c.1918C>G) pathogenic?

PTCD3 p.Pro640Ala (c.1918C>G) is classified Conflicting classifications of pathogenicity in PTCD3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-01). AlphaMissense: likely benign (0.1378); Rare (popmax 0.331%, amr); Associated with combined oxidative phosphorylation deficiency 51.

What condition is associated with PTCD3 p.Pro640Ala (c.1918C>G)?

PTCD3 p.Pro640Ala (c.1918C>G) is associated with combined oxidative phosphorylation deficiency 51 (ClinVar).

How common is PTCD3 p.Pro640Ala (c.1918C>G) in the general population?

PTCD3 p.Pro640Ala (c.1918C>G) is rare (popmax 0.331%, amr) (gnomAD).

What do computational predictors say about PTCD3 p.Pro640Ala (c.1918C>G)?

AlphaMissense predicts likely benign (score 0.1378) — an in-silico prediction, not a clinical call.

PTCD3 p.Pro640Ala

c.1918C>G · rs144692694 · VCV2651098

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1378 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.331%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined oxidative phosphorylation deficiency 51

Computational evidence

Protein change
AlphaMissense	0.1378	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -8.30	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 2.3	GERP 1.1, phastCons 0.9
Regional constraint	o/e 1.05	unconstrained · MANE · 31 kb · p 0.15 · regional, not allelic
Overall
CADD	19.05	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 0.331% Admixed American · 197/59,532 alleles

Filtering AF 0.293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.278%

Overall 0.14% 2,259/1,612,362 alleles · rare exomes 2,032/1,460,058 · genomes 227/152,304 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.331%	302
European (non-Finnish)	0.161%	622
Remaining individualsnot grpmax-eligible	0.15%	665
South Asian	0.0453%	2,209
African / African-American	0.0347%	2,884
Middle Eastern	0.0166%	6,042
Finnishnot grpmax-eligible	0.00469%	21,341

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: PTCD3
Protein: p.Pro640Ala
Coding: c.1918C>G
MANE Select: NM_017952
dbSNP: rs144692694
Type: single nucleotide variant
Location: chr2:86137079 (GRCh38)
Gene constraint: LOEUF 1.132 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 86 PDB
Residue 640: an α-helix

Full PTCD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined oxidative phosphorylation deficiency 51 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PTCD3 p.Arg524Leu Uncertain significance ★★ ⚠ same condition
PTCD3 c.1630-1G>A Likely pathogenic ★ same condition
PTCD3 c.1979+1G>A Likely pathogenic ★ same condition
PTCD3 c.805-2A>G Likely pathogenic ★ same condition
PTCD3 p.Trp477Ter Likely pathogenic ★ same condition
PTCD3 p.Gln214Ter Conflicting classifications of pathogenicity ★ same condition
PTCD3 p.Lys517Asn Uncertain significance ★ ⚠ same condition
PTCD3 p.Lys594= 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/ptcd3-p-pro640ala (accessed [today's date]).

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