Is ENDOU p.Arg368Ser (c.1104G>T) pathogenic?

ENDOU p.Arg368Ser (c.1104G>T) is classified Uncertain significance in ENDOU (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-16). AlphaMissense: ambiguous (0.4001); Ultra-rare (popmax 0.0334%, mid).

How common is ENDOU p.Arg368Ser (c.1104G>T) in the general population?

ENDOU p.Arg368Ser (c.1104G>T) is ultra-rare (popmax 0.0334%, mid) (gnomAD).

What do computational predictors say about ENDOU p.Arg368Ser (c.1104G>T)?

AlphaMissense predicts ambiguous (score 0.4001) — an in-silico prediction, not a clinical call.

ENDOU p.Arg368Ser

c.1104G>T · VCV3508477

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4001 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4001	ambiguous
REVEL	0.208	benign-leaning
SaProt	LLR -6.91	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.75	GERP -4, phastCons 0.006
Regional constraint	o/e 0.90	unconstrained · MANE · 15 kb · p 0.018 · regional, not allelic
Overall
CADD	21.7	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 0.0334% Middle Eastern · 2/5,984 alleles

Filtering AF 0.00589% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00245%

Overall 0.000372% 6/1,613,428 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0334%	2,992
African / African-American	0.004%	25,011
Admixed American	0.00167%	59,952

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.Arg368Ser
Coding: c.1104G>T
MANE Select: NM_001172439
Type: single nucleotide variant
Location: chr12:47711644 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.91 · 1 PDB
Residue 368: the endou domain

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-arg368ser (accessed [today's date]).

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