Is ENDOU p.Pro354Thr (c.1060C>A) pathogenic?

ENDOU p.Pro354Thr (c.1060C>A) is classified Uncertain significance in ENDOU (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-02). AlphaMissense: likely pathogenic (0.6745); Very rare (popmax 0.00833%, amr).

How common is ENDOU p.Pro354Thr (c.1060C>A) in the general population?

ENDOU p.Pro354Thr (c.1060C>A) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about ENDOU p.Pro354Thr (c.1060C>A)?

AlphaMissense predicts likely pathogenic (score 0.6745) — an in-silico prediction, not a clinical call.

ENDOU p.Pro354Thr

c.1060C>A · rs752819714 · VCV2304590

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6745 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6745	likely pathogenic
REVEL	0.643	indeterminate
SaProt	LLR -14.64	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 15 kb · p 0.018 · regional, not allelic
Overall
CADD	29.0	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 0.00833% Admixed American · 5/60,028 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.00041% 6/1,461,820 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,006
African / African-American	0.00133%	75,030

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: ENDOU
Protein: p.Pro354Thr
Coding: c.1060C>A
MANE Select: NM_001172439
dbSNP: rs752819714
Type: single nucleotide variant
Location: chr12:47711688 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.91 · 1 PDB
Residue 354: the endou domain; an α-helix

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

Similar variants

ENDOU p.Arg211Gln Benign ★★ same type
ENDOU p.Asp228= Benign ★★ same type
ENDOU p.Tyr317= Benign ★★ same type
ENDOU c.551+1G>A Uncertain significance ★ same type
ENDOU p.Ala229Val Uncertain significance ★ ⚠ same type
ENDOU p.Ala402Thr Uncertain significance ★ ⚠ same type
ENDOU p.Ala404Pro Uncertain significance ★ ⚠ same type
ENDOU p.Ala78Asp 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/endou-p-pro354thr (accessed [today's date]).

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