Is ECSIT p.Leu112Pro (c.335T>C) pathogenic?

ECSIT p.Leu112Pro (c.335T>C) is classified Uncertain significance in ECSIT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely pathogenic (0.8072); Very rare (popmax 0.00333%, amr).

How common is ECSIT p.Leu112Pro (c.335T>C) in the general population?

ECSIT p.Leu112Pro (c.335T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ECSIT p.Leu112Pro (c.335T>C)?

AlphaMissense predicts likely pathogenic (score 0.8072) — an in-silico prediction, not a clinical call.

ECSIT p.Leu112Pro

c.335T>C · VCV4016122

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8072 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8072	likely pathogenic · top 10% in ECSIT
REVEL	0.638	indeterminate
SaProt	LLR -13.08	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.44 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 13 kb · p 0.11 · regional, not allelic
Overall
CADD	27.5	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 0.00333% Admixed American · 2/60,000 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000372% 6/1,614,102 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,000
African / African-American	0.00267%	37,468
East Asian	0.00223%	44,892
European (non-Finnish)	8.47e-05%	1,180,045

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.Leu112Pro
Coding: c.335T>C
MANE Select: NM_016581
Type: single nucleotide variant
Location: chr19:11513983 (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-leu112pro (accessed [today's date]).

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