Is ECI2 p.Ala67Val (c.200C>T) pathogenic?

ECI2 p.Ala67Val (c.200C>T) is classified Uncertain significance in ECI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely pathogenic (0.7429); Very rare (popmax 0.00892%, eas).

How common is ECI2 p.Ala67Val (c.200C>T) in the general population?

ECI2 p.Ala67Val (c.200C>T) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about ECI2 p.Ala67Val (c.200C>T)?

AlphaMissense predicts likely pathogenic (score 0.7429) — an in-silico prediction, not a clinical call.

ECI2 p.Ala67Val

c.200C>T · VCV3506496

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7429 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7429	likely pathogenic
REVEL	0.413	indeterminate
SaProt	LLR -12.83	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 5.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 20 kb · p 0.84 · regional, not allelic
Overall
CADD	23.7	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 0.00892% East Asian · 4/44,844 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00313%

Overall 0.00428% 69/1,612,626 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0271%	3,694
East Asiangrpmax	0.00892%	11,211
South Asian	0.00881%	11,345
Admixed American	0.00502%	19,915
Remaining individualsnot grpmax-eligible	0.0048%	20,813
European (non-Finnish)	0.00339%	29,485
African / African-American	0.00267%	37,459
Finnishnot grpmax-eligible	0.00156%	63,984

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala67Val
Coding: c.200C>T
MANE Select: NM_206836
Type: single nucleotide variant
Location: chr6:4133562 (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.Ala67Thr 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-ala67val (accessed [today's date]).

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