Is EFCAB3 p.Arg99Ter (c.295C>T) pathogenic?

EFCAB3 p.Arg99Ter (c.295C>T) is classified Benign/Likely benign in EFCAB3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-03-01). Rare (popmax 0.707%, nfe).

How common is EFCAB3 p.Arg99Ter (c.295C>T) in the general population?

EFCAB3 p.Arg99Ter (c.295C>T) is rare (popmax 0.707%, nfe) (gnomAD).

EFCAB3 p.Arg99Ter

c.295C>T · rs61751980 · VCV787599

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.707%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 10
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.99	GERP -2.7
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.707% European (non-Finnish) · 8,252/1,167,432 alleles

Filtering AF 0.694% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.689%

Overall 0.735% 11,709/1,592,754 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	4.27%	23
European (non-Finnish)grpmax	0.707%	141
Remaining individualsnot grpmax-eligible	0.632%	158
Ashkenazi Jewishnot grpmax-eligible	0.248%	403
Admixed American	0.221%	452
South Asian	0.115%	867
African / African-American	0.0897%	1,115
Middle Eastern	0.0167%	5,972
East Asian	0.00448%	22,304

Finnish 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: EFCAB3
Protein: p.Arg99Ter
Coding: c.295C>T
MANE Select: NM_173503
dbSNP: rs61751980
Type: single nucleotide variant
Location: chr17:62391965 (GRCh38)
Gene constraint: LOEUF 1.102 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.80
Residue 99: the ef-hand 2 domain

Full EFCAB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFCAB3 c.34+6G>T Benign ★★ same type
EFCAB3 c.488+2T>C Benign ★★ same type
EFCAB3 p.Lys15Asn Benign ★★ same type
EFCAB3 p.Ser370Phe Benign ★★ same type
EFCAB3 c.-5G>A Uncertain significance ★ same type
EFCAB3 c.-8C>G Uncertain significance ★ same type
EFCAB3 p.Ala208Thr Uncertain significance ★ ⚠ same type
EFCAB3 p.Ala334Thr 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/efcab3-p-arg99ter (accessed [today's date]).

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