Is HID1 p.Phe520Ser (c.1559T>C) pathogenic?

HID1 p.Phe520Ser (c.1559T>C) is classified Uncertain significance in HID1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-05). AlphaMissense: likely pathogenic (0.8755); Absent from gnomAD v4.1.

How common is HID1 p.Phe520Ser (c.1559T>C) in the general population?

HID1 p.Phe520Ser (c.1559T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HID1 p.Phe520Ser (c.1559T>C)?

AlphaMissense predicts likely pathogenic (score 0.8755) — an in-silico prediction, not a clinical call.

HID1 p.Phe520Ser

c.1559T>C · rs2544475980 · VCV3105800

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8755 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8755	likely pathogenic
REVEL	0.568	indeterminate
SaProt	LLR -12.20	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.1	GERP 0.55, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 21 kb · p 9e-09 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HID1
Protein: p.Phe520Ser
Coding: c.1559T>C
MANE Select: NM_030630
dbSNP: rs2544475980
Type: single nucleotide variant
Location: chr17:74955869 (GRCh38)
Gene constraint: LOEUF 0.642 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.13
Residue 520: a UniProt-annotated variant site (in dee105; likely pathogenic)

Full HID1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HID1 p.Asp201Asn Uncertain significance ★★ same type
HID1 p.Ser87Leu Uncertain significance ★★ ⚠ same type
DMC1 p.Met200Val Benign ★★ ⚠ same type
HID1 c.1149+7C>T Benign ★★ same type
HID1 p.Gln130Glu Benign ★★ same type
HID1 p.His192Tyr Benign ★★ same type
HID1 c.1149+1G>T Likely pathogenic ★ same type
HID1 p.Arg668Ter Likely pathogenic ★ 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/hid1-p-phe520ser (accessed [today's date]).

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