Is PHIP p.Ser674Phe (c.2021C>T) pathogenic?

PHIP p.Ser674Phe (c.2021C>T) is classified Uncertain significance in PHIP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-09). AlphaMissense: likely benign (0.2846); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with PHIP p.Ser674Phe (c.2021C>T)?

PHIP p.Ser674Phe (c.2021C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PHIP p.Ser674Phe (c.2021C>T) in the general population?

PHIP p.Ser674Phe (c.2021C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about PHIP p.Ser674Phe (c.2021C>T)?

AlphaMissense predicts likely benign (score 0.2846) — an in-silico prediction, not a clinical call.

PHIP p.Ser674Phe

c.2021C>T · rs1769703046 · VCV2628822

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2846 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2846	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -9.52	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 12	GERP 1.1, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 11 kb · p 7.6e-13 · regional, not allelic
Overall
CADD	26.1	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 0.00134% African / African-American · 1/74,836 alleles

Overall 6.21e-05% 1/1,610,482 alleles · very rare exomes 1/1,458,274 · genomes 0/152,208 · joint denominator

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: PHIP
Protein: p.Ser674Phe
Coding: c.2021C>T
MANE Select: NM_017934
dbSNP: rs1769703046
Type: single nucleotide variant
Location: chr6:78997594 (GRCh38)
Gene constraint: LOEUF 0.246 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.57 · 146 PDB
Residue 674: the 'disordered' region; a modified residue (phosphoserine); a UniProt-annotated variant site (in chujans)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHIP p.Arg160Gly Uncertain significance ★★ ⚠ same condition
PHIP p.Arg346Gln Uncertain significance ★★ ⚠ same condition
PHIP p.Arg691Leu Uncertain significance ★★ ⚠ same condition
PHIP p.Arg799Ile Uncertain significance ★★ ⚠ same condition
PHIP p.Arg837Thr Uncertain significance ★★ ⚠ same condition
PHIP p.Asn795His Uncertain significance ★★ ⚠ same condition
PHIP p.Gln638Glu Uncertain significance ★★ ⚠ same condition
PHIP p.Gly412Ser 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/phip-p-ser674phe (accessed [today's date]).

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