Is ECI2 p.Pro279Leu (c.836C>T) pathogenic?

ECI2 p.Pro279Leu (c.836C>T) is classified Uncertain significance in ECI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: ambiguous (0.4925); Ultra-rare (popmax 0.0147%, afr).

How common is ECI2 p.Pro279Leu (c.836C>T) in the general population?

ECI2 p.Pro279Leu (c.836C>T) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about ECI2 p.Pro279Leu (c.836C>T)?

AlphaMissense predicts ambiguous (score 0.4925) — an in-silico prediction, not a clinical call.

ECI2 p.Pro279Leu

c.836C>T · VCV4246391

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4925 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4925	ambiguous
REVEL	0.674	pathogenic-leaning
SaProt	LLR -15.88	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 20 kb · p 0.84 · regional, not allelic
Overall
CADD	27.8	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 0.0147% African / African-American · 11/74,988 alleles

Filtering AF 0.00815% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00167% 27/1,613,702 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,817
Remaining individualsnot grpmax-eligible	0.008%	12,495
Admixed American	0.00167%	59,976
South Asian	0.0011%	91,044
European (non-Finnish)	0.000763%	131,094

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: ECI2
Protein: p.Pro279Leu
Coding: c.836C>T
MANE Select: NM_206836
Type: single nucleotide variant
Location: chr6:4119235 (GRCh38)
Gene constraint: LOEUF 0.949 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.40 · 5 PDB
Residue 279: the 'ech-like' region

Full ECI2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ECI2 p.Ala11Pro Uncertain significance ★ ⚠ same type
ECI2 p.Ala67Thr Uncertain significance ★ ⚠ same type
ECI2 p.Ala67Val Uncertain significance ★ ⚠ same type
ECI2 p.Ala7Val Uncertain significance ★ ⚠ same type
ECI2 p.Ala95Thr Uncertain significance ★ ⚠ same type
ECI2 p.Arg157Trp Uncertain significance ★ ⚠ same type
ECI2 p.Cys15Tyr Uncertain significance ★ ⚠ same type
ECI2 p.Glu147Lys 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/eci2-p-pro279leu (accessed [today's date]).

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