Is SEC63 p.Ile71Phe (c.211A>T) pathogenic?

SEC63 p.Ile71Phe (c.211A>T) is classified Uncertain significance in SEC63 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely benign (0.1008); Very rare (popmax 0.00221%, nfe); Associated with polycystic liver disease 2.

What condition is associated with SEC63 p.Ile71Phe (c.211A>T)?

SEC63 p.Ile71Phe (c.211A>T) is associated with polycystic liver disease 2 (ClinVar).

How common is SEC63 p.Ile71Phe (c.211A>T) in the general population?

SEC63 p.Ile71Phe (c.211A>T) is very rare (popmax 0.00221%, nfe) (gnomAD).

What do computational predictors say about SEC63 p.Ile71Phe (c.211A>T)?

AlphaMissense predicts likely benign (score 0.1008) — an in-silico prediction, not a clinical call.

SEC63 p.Ile71Phe

c.211A>T · VCV4532011

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1008 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

polycystic liver disease 2

Computational evidence

Protein change
AlphaMissense	0.1008	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -4.33	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 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 0.034 · regional, not allelic
Overall
CADD	21.1	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 0.00221% European (non-Finnish) · 25/1,131,316 alleles

Filtering AF 0.00152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00128%

Overall 0.00173% 27/1,560,298 alleles · very rare exomes 27/1,407,962 · genomes 0/152,336 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00221%	45,253
Remaining individualsnot grpmax-eligible	0.00165%	60,766
African / African-American	0.00135%	73,912

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: SEC63
Protein: p.Ile71Phe
Coding: c.211A>T
MANE Select: NM_007214
Type: single nucleotide variant
Location: chr6:107929428 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 71: a UniProt-annotated variant site (in pcld2)

Full SEC63 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

polycystic liver disease 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SEC63 c.452+1G>A Pathogenic/Likely pathogenic ★★ same condition
SEC63 c.625-2A>G Likely pathogenic ★★ same condition
SEC63 c.733+1G>A Pathogenic ★★ same condition
SEC63 p.Arg239Ter Pathogenic/Likely pathogenic ★★ same condition
SEC63 p.Arg622Ter Pathogenic/Likely pathogenic ★★ same condition
SEC63 p.Arg98Ter Pathogenic/Likely pathogenic ★★ same condition
SEC63 p.Ser632Ter Pathogenic/Likely pathogenic ★★ same condition
SEC63 c.452+3A>G Uncertain significance ★★ same condition

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/sec63-p-ile71phe (accessed [today's date]).

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