Is ENTHD1 p.Arg406Trp (c.1216C>T) pathogenic?

ENTHD1 p.Arg406Trp (c.1216C>T) is classified Likely benign in ENTHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-12). AlphaMissense: likely benign (0.0785); Ultra-rare (popmax 0.0402%, nfe).

How common is ENTHD1 p.Arg406Trp (c.1216C>T) in the general population?

ENTHD1 p.Arg406Trp (c.1216C>T) is ultra-rare (popmax 0.0402%, nfe) (gnomAD).

What do computational predictors say about ENTHD1 p.Arg406Trp (c.1216C>T)?

AlphaMissense predicts likely benign (score 0.0785) — an in-silico prediction, not a clinical call.

ENTHD1 p.Arg406Trp

c.1216C>T · rs547267116 · VCV2366008

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0785 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0402%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0785	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -8.01	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 -0.93	GERP -3.5
Regional constraint	o/e 0.88	unconstrained · MANE · 144 kb · p 0.0022 · regional, not allelic
Overall
CADD	3.876	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 0.0402% European (non-Finnish) · 471/1,171,054 alleles

Filtering AF 0.0371% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.036%

Overall 0.031% 494/1,595,608 alleles · ultra-rare exomes 470/1,444,146 · genomes 24/151,462 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0402%	2,486
Remaining individualsnot grpmax-eligible	0.0129%	7,725
African / African-American	0.00944%	10,591
South Asian	0.0056%	17,867
Admixed American	0.00345%	28,971
Ashkenazi Jewishnot grpmax-eligible	0.00342%	29,204

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: ENTHD1
Protein: p.Arg406Trp
Coding: c.1216C>T
MANE Select: NM_152512
dbSNP: rs547267116
Type: single nucleotide variant
Location: chr22:39765226 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.58

Full ENTHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENTHD1 p.Arg406Gln Likely benign ★ same residue
ENTHD1 p.Ala112Ser Uncertain significance ★ ⚠ same type
ENTHD1 p.Ala144Gly Uncertain significance ★ ⚠ same type
ENTHD1 p.Ala170Val Uncertain significance ★ ⚠ same type
ENTHD1 p.Ala385Gly Uncertain significance ★ ⚠ same type
ENTHD1 p.Arg121Trp Uncertain significance ★ ⚠ same type
ENTHD1 p.Arg141Met Uncertain significance ★ ⚠ same type
ENTHD1 p.Arg146Gln 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/enthd1-p-arg406trp (accessed [today's date]).

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