Is ECSIT p.Pro329Leu (c.986C>T) pathogenic?

ECSIT p.Pro329Leu (c.986C>T) is classified Likely benign in ECSIT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). AlphaMissense: ambiguous (0.5361); Very rare (popmax 0.00446%, eas).

How common is ECSIT p.Pro329Leu (c.986C>T) in the general population?

ECSIT p.Pro329Leu (c.986C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about ECSIT p.Pro329Leu (c.986C>T)?

AlphaMissense predicts ambiguous (score 0.5361) — an in-silico prediction, not a clinical call.

ECSIT p.Pro329Leu

c.986C>T · VCV4016116

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5361 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Computational evidence

Protein change
AlphaMissense	0.5361	ambiguous
REVEL	0.295	indeterminate
SaProt	LLR -8.62	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 13 kb · p 0.11 · regional, not allelic
Overall
CADD	24.9	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 0.00446% East Asian · 2/44,884 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000434% 7/1,613,904 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,442
South Asian	0.0022%	45,538
African / African-American	0.00134%	74,858
European (non-Finnish)	0.000169%	590,009

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: ECSIT
Protein: p.Pro329Leu
Coding: c.986C>T
MANE Select: NM_016581
Type: single nucleotide variant
Location: chr19:11507522 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.35 · 1 PDB

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

Similar variants

ECSIT p.Ala45Val Uncertain significance ★ ⚠ same type
ECSIT p.Ala47Ser Uncertain significance ★ ⚠ same type
ECSIT p.Ala79Val Uncertain significance ★ ⚠ same type
ECSIT p.Ala97Val Uncertain significance ★ ⚠ same type
ECSIT p.Arg104Trp Uncertain significance ★ ⚠ same type
ECSIT p.Arg115Cys Uncertain significance ★ ⚠ same type
ECSIT p.Arg118Trp Uncertain significance ★ ⚠ same type
ECSIT p.Arg11Gln 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/ecsit-p-pro329leu (accessed [today's date]).

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