Is EID2B p.Pro136Ala (c.406C>G) pathogenic?

EID2B p.Pro136Ala (c.406C>G) is classified Uncertain significance in EID2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: ambiguous (0.4601); Very rare (popmax 0.00267%, afr).

How common is EID2B p.Pro136Ala (c.406C>G) in the general population?

EID2B p.Pro136Ala (c.406C>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about EID2B p.Pro136Ala (c.406C>G)?

AlphaMissense predicts ambiguous (score 0.4601) — an in-silico prediction, not a clinical call.

EID2B p.Pro136Ala

c.406C>G · VCV4247626

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4601 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4601	ambiguous
REVEL	0.15	moderately benign-leaning
SaProt	LLR -9.41	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 2.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 482 bp · p 0.69 · regional, not allelic
Overall
CADD	20.6	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 0.00267% African / African-American · 2/74,944 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000867% 14/1,614,066 alleles · very rare exomes 12/1,461,832 · genomes 2/152,234 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,472
European (non-Finnish)	0.00102%	98,338

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: EID2B
Protein: p.Pro136Ala
Coding: c.406C>G
MANE Select: NM_152361
Type: single nucleotide variant
Location: chr19:39532397 (GRCh38)
Gene constraint: LOEUF 1.759 · pLI 0.24 (gnomAD)
Structure: AlphaFold pLDDT 70.26

Full EID2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EID2B p.Ala131Val Uncertain significance ★ ⚠ same type
EID2B p.Ala134Thr Uncertain significance ★ ⚠ same type
EID2B p.Ala143Ser Uncertain significance ★ ⚠ same type
EID2B p.Ala45Thr Uncertain significance ★ ⚠ same type
EID2B p.Ala45Val Uncertain significance ★ ⚠ same type
EID2B p.Arg119Lys Uncertain significance ★ ⚠ same type
EID2B p.Gln83Pro Uncertain significance ★ ⚠ same type
EID2B p.Gln84Arg 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/eid2b-p-pro136ala (accessed [today's date]).

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