Is ECI2 p.Ala67Thr (c.199G>A) pathogenic?

ECI2 p.Ala67Thr (c.199G>A) is classified Uncertain significance in ECI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-17). AlphaMissense: likely pathogenic (0.5919); Very rare (popmax 0.00335%, amr).

How common is ECI2 p.Ala67Thr (c.199G>A) in the general population?

ECI2 p.Ala67Thr (c.199G>A) is very rare (popmax 0.00335%, amr) (gnomAD).

What do computational predictors say about ECI2 p.Ala67Thr (c.199G>A)?

AlphaMissense predicts likely pathogenic (score 0.5919) — an in-silico prediction, not a clinical call.

ECI2 p.Ala67Thr

c.199G>A · rs758489249 · VCV2537087

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5919 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00335%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5919	likely pathogenic
REVEL	0.396	indeterminate
SaProt	LLR -10.24	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 3.1	GERP -1.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 20 kb · p 0.84 · regional, not allelic
Overall
CADD	22.5	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 0.00335% Admixed American · 2/59,716 alleles

Filtering AF 0.000556% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000992% 16/1,612,512 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00335%	29,858
South Asian	0.0022%	45,372
African / African-American	0.00134%	74,826
European (non-Finnish)	0.000933%	107,221

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.Ala67Thr
Coding: c.199G>A
MANE Select: NM_206836
dbSNP: rs758489249
Type: single nucleotide variant
Location: chr6:4133563 (GRCh38)
Gene constraint: LOEUF 0.949 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.40 · 5 PDB
Residue 67: the acb domain; an α-helix; a binding site

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

Similar variants

ECI2 p.Ala67Val Uncertain significance ★ ⚠ same residue
ECI2 p.Ala11Pro 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
ECI2 p.Glu60Lys 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-ala67thr (accessed [today's date]).

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