Is EFCAB13 p.Pro136Ser (c.406C>T) pathogenic?

EFCAB13 p.Pro136Ser (c.406C>T) is classified Uncertain significance in EFCAB13 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.1275); Very rare (popmax 0.00267%, afr).

How common is EFCAB13 p.Pro136Ser (c.406C>T) in the general population?

EFCAB13 p.Pro136Ser (c.406C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about EFCAB13 p.Pro136Ser (c.406C>T)?

AlphaMissense predicts likely benign (score 0.1275) — an in-silico prediction, not a clinical call.

EFCAB13 p.Pro136Ser

c.406C>T · rs755943359 · VCV2383369

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1275 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1275	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -4.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.057
Regional constraint	o/e 0.86	unconstrained · MANE · 112 kb · p 6e-06 · regional, not allelic
Overall
CADD	10.05	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00267% African / African-American · 2/74,852 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00105% 17/1,612,354 alleles · very rare exomes 14/1,460,228 · genomes 3/152,126 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0305%	3,284
Remaining individualsnot grpmax-eligible	0.0032%	31,214
African / African-Americangrpmax	0.00267%	37,426
European (non-Finnish)	0.000339%	294,736

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: EFCAB13
Protein: p.Pro136Ser
Coding: c.406C>T
MANE Select: NM_152347
dbSNP: rs755943359
Type: single nucleotide variant
Location: chr17:47344264 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 53.37

Full EFCAB13 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFCAB13 p.Ala453Val Uncertain significance ★ ⚠ same type
EFCAB13 p.Ala605Gly Uncertain significance ★ ⚠ same type
EFCAB13 p.Ala668Asp Uncertain significance ★ ⚠ same type
EFCAB13 p.Ala680Val Uncertain significance ★ ⚠ same type
EFCAB13 p.Ala750Ser Uncertain significance ★ ⚠ same type
EFCAB13 p.Arg185Gln Uncertain significance ★ ⚠ same type
EFCAB13 p.Arg236Gln Uncertain significance ★ ⚠ same type
EFCAB13 p.Arg255Cys 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/efcab13-p-pro136ser (accessed [today's date]).

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