Is EFHC2 p.Arg605Cys (c.1813C>T) pathogenic?

EFHC2 p.Arg605Cys (c.1813C>T) is classified Uncertain significance in EFHC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-09). AlphaMissense: ambiguous (0.5518); Very rare (popmax 0.00175%, afr).

How common is EFHC2 p.Arg605Cys (c.1813C>T) in the general population?

EFHC2 p.Arg605Cys (c.1813C>T) is very rare (popmax 0.00175%, afr) (gnomAD).

What do computational predictors say about EFHC2 p.Arg605Cys (c.1813C>T)?

AlphaMissense predicts ambiguous (score 0.5518) — an in-silico prediction, not a clinical call.

EFHC2 p.Arg605Cys

c.1813C>T · VCV3843666

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5518 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5518	ambiguous
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -8.07	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 3.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 195 kb · p 0.037 · regional, not allelic
Overall
CADD	26.3	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 0.00175% African / African-American · 1/57,195 alleles

Filtering AF 0.000105% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.1e-05%

Overall 0.000582% 7/1,203,521 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00458%	21,834
Remaining individualsnot grpmax-eligible	0.00211%	47,410
African / African-Americangrpmax	0.00175%	57,195
European (non-Finnish)	0.000448%	223,250

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: EFHC2
Protein: p.Arg605Cys
Coding: c.1813C>T
MANE Select: NM_025184
Type: single nucleotide variant
Location: chrX:44178503 (GRCh38)
Structure: AlphaFold pLDDT 79.83 · 4 PDB

Full EFHC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFHC2 p.Glu506Lys Likely benign ★★ ⚠ same type
EFHC2 p.Glu507Gln Benign ★★ ⚠ same type
EFHC2 p.Ala549Gly Uncertain significance ★ ⚠ same type
EFHC2 p.Ala697Ser Uncertain significance ★ ⚠ same type
EFHC2 p.Arg133His Uncertain significance ★ ⚠ same type
EFHC2 p.Arg135Gln Conflicting classifications of pathogenicity ★ ⚠ same type
EFHC2 p.Arg135Trp Uncertain significance ★ ⚠ same type
EFHC2 p.Arg163Gln 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/efhc2-p-arg605cys (accessed [today's date]).

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