Is PTCHD1 p.Leu415Phe (c.1243C>T) pathogenic?

PTCHD1 p.Leu415Phe (c.1243C>T) is classified Uncertain significance in PTCHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-06-23). AlphaMissense: likely benign (0.1493); Very rare (popmax 0.00654%, amr).

How common is PTCHD1 p.Leu415Phe (c.1243C>T) in the general population?

PTCHD1 p.Leu415Phe (c.1243C>T) is very rare (popmax 0.00654%, amr) (gnomAD).

What do computational predictors say about PTCHD1 p.Leu415Phe (c.1243C>T)?

AlphaMissense predicts likely benign (score 0.1493) — an in-silico prediction, not a clinical call.

PTCHD1 p.Leu415Phe

c.1243C>T · rs1277116747 · VCV450030

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1493 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00654%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1493	likely benign
REVEL	0.343	indeterminate
SaProt	LLR -6.49	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 59 kb · p 4.1e-12 · regional, not allelic
Overall
CADD	18.89	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 0.00654% Admixed American · 3/45,846 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000881%

Overall 0.000744% 9/1,209,518 alleles · very rare exomes 7/1,097,004 · genomes 2/112,514 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00654%	15,282
Remaining individualsnot grpmax-eligible	0.0042%	23,785
European (non-Finnish)	0.000447%	223,579

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: PTCHD1
Protein: p.Leu415Phe
Coding: c.1243C>T
MANE Select: NM_173495
dbSNP: rs1277116747
Type: single nucleotide variant
Location: chrX:23392761 (GRCh38)
Structure: AlphaFold pLDDT 84.14
Residue 415: the ssd domain

Full PTCHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PTCHD1 p.Pro32Arg Likely pathogenic ★★ same type
PTCHD1 p.Ala314Thr Uncertain significance ★★ ⚠ same type
PTCHD1 p.Arg238Ser Uncertain significance ★★ ⚠ same type
PTCHD1 p.Arg266= Uncertain significance ★★ same type
PTCHD1 p.Arg294His Uncertain significance ★★ ⚠ same type
PTCHD1 p.Arg596Trp Uncertain significance ★★ ⚠ same type
PTCHD1 p.Asn818Ser Uncertain significance ★★ ⚠ same type
PTCHD1 p.Asp663His 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/ptchd1-p-leu415phe (accessed [today's date]).

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